一种新型的PI3Kα/mTOR双抑制剂PI-103的抗肿瘤活性研究
|
摘要
恶性肿瘤严重威胁着人类的健康和生命,其中肺癌是死亡率和发病率都居于第一位的恶性肿瘤。结肠癌和原发性肝癌也是常见的恶性肿瘤,其发病率和死亡率也都居于恶性肿瘤的前列。目前对于恶性肿瘤的治疗方法还是传统的手术、化疗和放疗,但由于传统的肿瘤治疗方法无靶向特异性,在杀死肿瘤细胞的同时往往也会导致正常组织的损伤,从而有很强的副作用。随着肿瘤分子生物学的发展,针对恶性肿瘤的分子事件的靶向治疗越来越受到人们的重视。靶向治疗以及复合疗法将为恶性肿瘤的治疗开辟新的治疗途径。近年来的研究发现,PI3K/Akt/mTOR和Ras/Erk信号通路在肿瘤细胞生长、增殖、侵袭和转移中起关键作用,阻断细胞内相应的信号通路能抑制肿瘤细胞生长甚至促进肿瘤细胞凋亡。PI-103是由加州大学旧金山分校的研究人员合成的一种PI3Kα/mTOR抑制双靶点抑制剂,U0126是MEK激酶的抑制剂,两种抑制剂目前都处于细胞实验阶段,还没有用于临床肿瘤治疗。其中PI-103购自德国Merck公司,U0126购自Sigma公司。本文研究了PI-103单用以及和MEK抑制剂U0126、化疗药物紫杉醇和多不饱和脂肪酸DHA联用在非小细胞肺癌、肝癌和结肠癌中的抗癌效果。结果如下：
1.研究发现在非小细胞肺癌A549细胞和H460细胞中,双抑制剂PI-103有显著的抗癌活性。PI-103在PIK3CA基因(该基因编码PI3K蛋白的催化单元p110α)突变的H460细胞有更明显的抗肿瘤作用。在A549和H460细胞中,PI-103和MEK抑制剂U0126联用其药物联用指数CI＜1,表明这两种药物有协同诱导细胞生长抑制的作用。PI-103和U0126协同诱导细胞生长抑制作用主要是通过阻断细胞内PI3K/Akt/mTOR和Ras/Erk通路,而且PI-103阻断了因雷帕霉素抑制nTOR而导致的Akt活化。研究发现PI3K/Akt/mTOR和Ras/Erk通路会共同作用于mTOR激酶。而且发现PI-103和U0126联用能同时抑制核糖体蛋白s6和真核起始因子4B(eIF4B)的磷酸化,从而抑制翻译复合物的组装和翻译起始,最终协同诱导细胞生长抑制,解释了为什么PI-103和U0126能协同诱导细胞的生长抑制。
2.在A549细胞和H460细胞中,PI-103诱导了G0／G1期细胞周期停滞,和在A549细胞中相比,PI-103在H460细胞中诱导更明显的细胞周期停滞。PI-103和U0126联用协同诱导了G0／G1期细胞周期停滞。PI-103和U0126联用协同诱导的G0／G1期细胞周期停滞与细胞内G0／G1期相关周期调节蛋白改变有关,如细胞周期激酶抑制因子p21和p27上调,以及细胞周期蛋白cyclin D1和cyclin E1下调。
3.PI-103不仅在A549和H460细胞中协同加强了紫杉醇的细胞生长抑制作用,而且也协同加强了紫杉醇诱导的细胞凋亡。PI-103和紫杉醇联用诱导的细胞凋亡与细胞内凋亡蛋白协同改变有关,紫杉醇和PI-103联用和单用相比,肿瘤抑制因子p53和促凋亡蛋白Bad显著上调,抗凋亡蛋白Bcl-2显著下调。这些凋亡相关蛋白的改变诱发了线粒体凋亡相关途径,从而导致细胞凋亡。PI-103作为第一种合成的PI3Kα/mTOR双抑制剂,其单用或者与U0126、紫杉醇联用都在非小细胞肺癌细胞A549和H460中显示了明显的抗癌活性。表明了复合治疗是一种有效的肿瘤治疗策略。我们的研究为吉非替尼抗性的非小细胞肺癌提供了一种崭新的治疗方案。
4.同时我们也研究了PI-103在结肠癌细胞系CaCO2和肝癌细胞系HepG2中的抗癌效果,发现PI-103单用也能明显地抑制CaCO2和HepG2细胞的生长。而且PI-103和U0126联用也能协同诱导细胞生长抑制。在HepG2细胞中,PI-103和U0126也协同诱导了G0／G1期细胞周期停滞。PI-103同样能协同加强化疗药物紫杉醇诱导的细胞凋亡作用。也说明PI-103在结肠癌和肝癌中,是一种潜在的靶向治疗药物。我们的研究也同样为结肠癌和肝癌的临床治疗提供了潜在的治疗方案。
5.DHA的抗癌活性与脂质过氧化有关,脂质过氧化产物对细胞有毒性从而抑制肿瘤细胞生长。另一方面DHA发生脂质过氧化因而减少了膜上DHA的水平,导致膜上磷脂酰丝氨酸减少,抑制了细胞内PI3K/Akt信号通路转导,从而抑制肿瘤细胞生长。血清能明显拮抗DHA的抗癌作用,10%的血清下,DHA反而促进肿瘤细胞生长,可能是血清中的生长因子或者牛血清白蛋白阻碍了膜上富集的DHA发生脂质过氧化反应,从而促进了细胞存活通路PI3K/Akt的信号转导。PI-103通过阻断磷脂酰丝氨酸介导的PI3K/Akt信号传导,有效地拮抗了DHA在正常培养下对A549细胞的生长促进作用。我们的研究进一步阐明了DHA的抗癌机制,而且为DHA作为一种辅助抗癌药物的研发具有一定的指导意义。
Lung cancer is the leading cause of morbility and mortality of malignant tumors which seriously threat our health and lives. Colon cancer and primary hepatic carcinoma are also two common malignant tumors, which are characterized with high morbility and mortality. The major therapeutics of malignant tumors is surgery, traditional chemotherapy and radiotherapy. Traditional tumor therapies show high side-effects due to theirs non-specificity, which not only kill tumor cells but do harm to normal tissue. With the development of tumor molecular biology, tumor targeted therapy become increasingly important for cancer therapy, targeted therapy and compound therapy will provide several promising strategies for cancer therapy. In the recent years, a series of studies have shown that PI3K/Akt/mTOR and Ras/Erk signaling pathways play a key role in growth, proliferation, invasion and metastasis of cancer cells. Blockade of the two pathways will induce growth inhibition and apoptosis. The novel PI3Ka/mTOR dual inhibitor was synthesized by scientists in University of California in San Francisco, U0126 is the MEK kinase inhibitor. These two inhibitors are being used in preclinical experiments. PI-103 was purchased from Merck company, and U0126 from Sigma company. In the present study, the antitumor activity of PI-103 alone or in combination with U0126, paclitaxel and DHA was observed in non-small lung cancer cell line A549 and H460, colon caner cell line CaCO2 and hepatic carcinoma cell line HepG2. The results were presented as follows:
1. PI-103, the novel PI3Kα/mTOR dual inhibitor showed high antitumor effects in A549 and H460 cells. H460 cells with activating mutations of PIK3CA, the gene encoding the p110αcatalytic subunit of PI3K, were more sensitive to low-dose PI-103. The CI value of PI-103 in combination with U0126 was less than one, suggesting that the combination of PI-103 and U0126 acted synergistically to induce growth inhibition. The synergistic antitumor effects were derived from concomitant inhibition of the PI3K/Akt/mTOR and Ras/Erk signaling pathways. Additionally, Akt phosphorylation induced by mTOR inhibition with rapamycin was inhibited by PI-103. We also found that mTOR functions downstream of Akt and Erk. The phosphorylation of ribosomal protein s6 and the eukaryotic translation initiation factor 4B (eIF4B) was concomitantly inhibited by PI-103 and U0126, which may cooperatively inhibited translation initiation complex assembly and translation initiation. This data explained why blockade of the PI3K/Akt/mTOR and Ras/Erk shows synergistic antitumor effects.
2. G0/G1 arrest was induced by PI-103 in A549 and H460 cells, and H460 cells were more sensitive to PI-103. PI-103 synergized with U0126 to induce G0/G1 arrest in A549 and H460 cells. Our results showed that PI-103 or U0126 exerts its effects on cell cycle progression via the upregulation of p21 and p27, and the simultaneous downregulation of cyclin D1 and cyclin E1. The synergistic antiproliferative effects of PI-103 in combination with U0126 were derived from markedly up-regulating p21 and p27 protein levels, and significantly inhibiting the expression of cyclin D1 and cyclin E1.
3. PI-103 not only potentiated paclitaxel-induced growth inhibition but also enhanced paclitaxel-induced apoptosis in A549 and H460 cells. Apoptosis induced by paclitaxel and PI-103 was related to alterations of apoptosis proteins. Compared with treatment of paclitaxel alone, the combination of PI-103 and paclitaxel significantly up-regulated tumor suppressor P53 and pro-apoptosis protein Bad, and simultaneously down-regulated anti-apoptosis protein Bcl-2. Alterations of these apoptosis-related proteins finally triggered mitochondrial-related apoptosis pathway and led to cell apoptosis. Our study showed that compound therapy is the most effective tumor therapeutics, and provide a potential therapy strategy for gefitinib-resistant non-small cell lung cancer.
4. High antitumor activity of PI-103 was also showed in CaCO2 and HepG2 cells. PI-103 in combination with U0126 also showed synergistic antiproliferative effects with induction of G0/G1 arrest in CaCO2 and HepG2 cells. We also observed that Paclitaxel-induced apoptosis was enhanced by PI-103 in HepG2 cells. Our study suggested that PI-103 alone or in combination with other kinase inhibitors, or chemotherapy agents is a promising therapeutics for treating colon cancer and hepatic carcinoma.
5. The antitumor effects of Docosahexaenic Acid (DHA) were associated with lipid peroxidation. Lipid peroxidation may decrease DHA levels in cell membrane and lead to reduced phosphatidylserine in intracellular membrane, which blocks the PI3K/Akt signaling pathway and leads to cell growth inhibition. Antitumor effects of DHA were significantly antagonisted by serum. High-concentration DHA promoted cell growth in A549 cells in culture with 10% FBS. It is possible that growth factors or BSA impedes the lipid peroxidation of DHA enriched in plasma membrane and promotes the signaling of the PI3K/Akt pathway, which is attenuated by PI-103. Our study further elucidated the antitumor mechanism of DHA and provided meaningful directions for development of DHA as an adjuvant antitumor agent.
1.研究发现在非小细胞肺癌A549细胞和H460细胞中,双抑制剂PI-103有显著的抗癌活性。PI-103在PIK3CA基因(该基因编码PI3K蛋白的催化单元p110α)突变的H460细胞有更明显的抗肿瘤作用。在A549和H460细胞中,PI-103和MEK抑制剂U0126联用其药物联用指数CI＜1,表明这两种药物有协同诱导细胞生长抑制的作用。PI-103和U0126协同诱导细胞生长抑制作用主要是通过阻断细胞内PI3K/Akt/mTOR和Ras/Erk通路,而且PI-103阻断了因雷帕霉素抑制nTOR而导致的Akt活化。研究发现PI3K/Akt/mTOR和Ras/Erk通路会共同作用于mTOR激酶。而且发现PI-103和U0126联用能同时抑制核糖体蛋白s6和真核起始因子4B(eIF4B)的磷酸化,从而抑制翻译复合物的组装和翻译起始,最终协同诱导细胞生长抑制,解释了为什么PI-103和U0126能协同诱导细胞的生长抑制。
2.在A549细胞和H460细胞中,PI-103诱导了G0／G1期细胞周期停滞,和在A549细胞中相比,PI-103在H460细胞中诱导更明显的细胞周期停滞。PI-103和U0126联用协同诱导了G0／G1期细胞周期停滞。PI-103和U0126联用协同诱导的G0／G1期细胞周期停滞与细胞内G0／G1期相关周期调节蛋白改变有关,如细胞周期激酶抑制因子p21和p27上调,以及细胞周期蛋白cyclin D1和cyclin E1下调。
3.PI-103不仅在A549和H460细胞中协同加强了紫杉醇的细胞生长抑制作用,而且也协同加强了紫杉醇诱导的细胞凋亡。PI-103和紫杉醇联用诱导的细胞凋亡与细胞内凋亡蛋白协同改变有关,紫杉醇和PI-103联用和单用相比,肿瘤抑制因子p53和促凋亡蛋白Bad显著上调,抗凋亡蛋白Bcl-2显著下调。这些凋亡相关蛋白的改变诱发了线粒体凋亡相关途径,从而导致细胞凋亡。PI-103作为第一种合成的PI3Kα/mTOR双抑制剂,其单用或者与U0126、紫杉醇联用都在非小细胞肺癌细胞A549和H460中显示了明显的抗癌活性。表明了复合治疗是一种有效的肿瘤治疗策略。我们的研究为吉非替尼抗性的非小细胞肺癌提供了一种崭新的治疗方案。
4.同时我们也研究了PI-103在结肠癌细胞系CaCO2和肝癌细胞系HepG2中的抗癌效果,发现PI-103单用也能明显地抑制CaCO2和HepG2细胞的生长。而且PI-103和U0126联用也能协同诱导细胞生长抑制。在HepG2细胞中,PI-103和U0126也协同诱导了G0／G1期细胞周期停滞。PI-103同样能协同加强化疗药物紫杉醇诱导的细胞凋亡作用。也说明PI-103在结肠癌和肝癌中,是一种潜在的靶向治疗药物。我们的研究也同样为结肠癌和肝癌的临床治疗提供了潜在的治疗方案。
5.DHA的抗癌活性与脂质过氧化有关,脂质过氧化产物对细胞有毒性从而抑制肿瘤细胞生长。另一方面DHA发生脂质过氧化因而减少了膜上DHA的水平,导致膜上磷脂酰丝氨酸减少,抑制了细胞内PI3K/Akt信号通路转导,从而抑制肿瘤细胞生长。血清能明显拮抗DHA的抗癌作用,10%的血清下,DHA反而促进肿瘤细胞生长,可能是血清中的生长因子或者牛血清白蛋白阻碍了膜上富集的DHA发生脂质过氧化反应,从而促进了细胞存活通路PI3K/Akt的信号转导。PI-103通过阻断磷脂酰丝氨酸介导的PI3K/Akt信号传导,有效地拮抗了DHA在正常培养下对A549细胞的生长促进作用。我们的研究进一步阐明了DHA的抗癌机制,而且为DHA作为一种辅助抗癌药物的研发具有一定的指导意义。
Lung cancer is the leading cause of morbility and mortality of malignant tumors which seriously threat our health and lives. Colon cancer and primary hepatic carcinoma are also two common malignant tumors, which are characterized with high morbility and mortality. The major therapeutics of malignant tumors is surgery, traditional chemotherapy and radiotherapy. Traditional tumor therapies show high side-effects due to theirs non-specificity, which not only kill tumor cells but do harm to normal tissue. With the development of tumor molecular biology, tumor targeted therapy become increasingly important for cancer therapy, targeted therapy and compound therapy will provide several promising strategies for cancer therapy. In the recent years, a series of studies have shown that PI3K/Akt/mTOR and Ras/Erk signaling pathways play a key role in growth, proliferation, invasion and metastasis of cancer cells. Blockade of the two pathways will induce growth inhibition and apoptosis. The novel PI3Ka/mTOR dual inhibitor was synthesized by scientists in University of California in San Francisco, U0126 is the MEK kinase inhibitor. These two inhibitors are being used in preclinical experiments. PI-103 was purchased from Merck company, and U0126 from Sigma company. In the present study, the antitumor activity of PI-103 alone or in combination with U0126, paclitaxel and DHA was observed in non-small lung cancer cell line A549 and H460, colon caner cell line CaCO2 and hepatic carcinoma cell line HepG2. The results were presented as follows:
1. PI-103, the novel PI3Kα/mTOR dual inhibitor showed high antitumor effects in A549 and H460 cells. H460 cells with activating mutations of PIK3CA, the gene encoding the p110αcatalytic subunit of PI3K, were more sensitive to low-dose PI-103. The CI value of PI-103 in combination with U0126 was less than one, suggesting that the combination of PI-103 and U0126 acted synergistically to induce growth inhibition. The synergistic antitumor effects were derived from concomitant inhibition of the PI3K/Akt/mTOR and Ras/Erk signaling pathways. Additionally, Akt phosphorylation induced by mTOR inhibition with rapamycin was inhibited by PI-103. We also found that mTOR functions downstream of Akt and Erk. The phosphorylation of ribosomal protein s6 and the eukaryotic translation initiation factor 4B (eIF4B) was concomitantly inhibited by PI-103 and U0126, which may cooperatively inhibited translation initiation complex assembly and translation initiation. This data explained why blockade of the PI3K/Akt/mTOR and Ras/Erk shows synergistic antitumor effects.
2. G0/G1 arrest was induced by PI-103 in A549 and H460 cells, and H460 cells were more sensitive to PI-103. PI-103 synergized with U0126 to induce G0/G1 arrest in A549 and H460 cells. Our results showed that PI-103 or U0126 exerts its effects on cell cycle progression via the upregulation of p21 and p27, and the simultaneous downregulation of cyclin D1 and cyclin E1. The synergistic antiproliferative effects of PI-103 in combination with U0126 were derived from markedly up-regulating p21 and p27 protein levels, and significantly inhibiting the expression of cyclin D1 and cyclin E1.
3. PI-103 not only potentiated paclitaxel-induced growth inhibition but also enhanced paclitaxel-induced apoptosis in A549 and H460 cells. Apoptosis induced by paclitaxel and PI-103 was related to alterations of apoptosis proteins. Compared with treatment of paclitaxel alone, the combination of PI-103 and paclitaxel significantly up-regulated tumor suppressor P53 and pro-apoptosis protein Bad, and simultaneously down-regulated anti-apoptosis protein Bcl-2. Alterations of these apoptosis-related proteins finally triggered mitochondrial-related apoptosis pathway and led to cell apoptosis. Our study showed that compound therapy is the most effective tumor therapeutics, and provide a potential therapy strategy for gefitinib-resistant non-small cell lung cancer.
4. High antitumor activity of PI-103 was also showed in CaCO2 and HepG2 cells. PI-103 in combination with U0126 also showed synergistic antiproliferative effects with induction of G0/G1 arrest in CaCO2 and HepG2 cells. We also observed that Paclitaxel-induced apoptosis was enhanced by PI-103 in HepG2 cells. Our study suggested that PI-103 alone or in combination with other kinase inhibitors, or chemotherapy agents is a promising therapeutics for treating colon cancer and hepatic carcinoma.
5. The antitumor effects of Docosahexaenic Acid (DHA) were associated with lipid peroxidation. Lipid peroxidation may decrease DHA levels in cell membrane and lead to reduced phosphatidylserine in intracellular membrane, which blocks the PI3K/Akt signaling pathway and leads to cell growth inhibition. Antitumor effects of DHA were significantly antagonisted by serum. High-concentration DHA promoted cell growth in A549 cells in culture with 10% FBS. It is possible that growth factors or BSA impedes the lipid peroxidation of DHA enriched in plasma membrane and promotes the signaling of the PI3K/Akt pathway, which is attenuated by PI-103. Our study further elucidated the antitumor mechanism of DHA and provided meaningful directions for development of DHA as an adjuvant antitumor agent.
引文
[1]Cantley, L.C. (2002). The Phosphoinositide 3-Kinase Pathway. Science 296,1655-1657.
[2]Fruman, D.A., Meyers, R.E. and Cantley, L.C. (1998). Phosphoinositide kinases. Annu Rev Biochem 67,481-507.
[3]Hiles, I.D. et al. (1992). Phosphatidylinositol 3-kinase:structure and expression of the 110 kd catalytic subunit. Cell 70,419-429.
[4]Jimenez, C. et al. (1998). Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. Embo J 17,743-753.
[5]Pawson, T. and Nash, P. (2000). Protein-protein interactions define specificity in signal transduction. Genes Dev 14,1027-1047.
[6]Macara, I.G., Marinetti, G.V. and Balduzzi, P.C. (1984). Transforming Protein of Avian-Sarcoma Virus Ur2 Is Associated with Phosphatidylinositol Kinase-Activity Possible Role in Tumorigenesis. Proc Natl Acad Sci U S A 81,2728-2732.
[7]Sugimoto, Y., Whitman, M., Cantley, L.C. and Erikson, R.L. (1984). Evidence That the Rous-Sarcoma Virus Transforming Gene-Product Phosphorylates Phosphatidylinositol and Diacylglycerol. Proc Natl Acad Sci U S A 81,2117-2121.
[8]Whitman, M., Kaplan, D.R., Schaffhausen, B., Cantley, L. and Roberts, T.M. (1985). Association of Phosphatidylinositol Kinase-Activity with Polyoma Middle-T Competent for Transformation. Nature 315,239-242.
[9]Vanhaesebroeck, B. et al. (2001). Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70,535-602.
[10]Wymann, M.P. and Pirola, L. (1998). Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1436,127-150.
[11]Vivanco, I. and Sawyers, C.L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2,489-501.
[12]Bi, L., Okabe, I., Bernard, D.J., Wynshaw-Boris, A. and Nussbaum, R.L. (1999). Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 274,10963-10968.
[13]Bilancio, A., Okkenhaug, K., Camps, M., Emery, J.L., Ruckle, T., Rommel, C. and Vanhaesebroeck, B. (2006). Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling:comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107,642-650.
[14]Campbell, M., Allen, W.E., Sawyer, C., Vanhaesebroeck, B. and Trimble, E.R. (2004). Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res 95,380-388.
[15]Condliffe, A.M. et al. (2005). Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106,1432-1440.
[16]Northcott, C.A., Hayflick, J. and Watts, S.W. (2005). Upregulated function of phosphatidylinositol-3-kinase in genetically hypertensive rats:a moderator of arterial hypercontractility. Clin Exp Pharmacol Physiol 32,851-858.
[17]Sujobert, P. et al. (2005). Essential role for the pllOdelta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106, 1063-1066.
[18]Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D.A., Wood, C., Gray, P.W., Cooper, J.A. and Hoekstra, M.F. (1997). p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272,19236-19241.
[19]Jackson, S.P. et al. (2005). PI 3-kinase p110beta:a new target for antithrombotic therapy. Nat Med 11,507-514.
[20]Leverrier, Y., Okkenhaug, K., Sawyer, C., Bilancio, A., Vanhaesebroeck, B. and Ridley, A.J. (2003). Class I phosphoinositide 3-kinase p110beta is required for apoptotic cell and Fcgamma receptor-mediated phagocytosis by macrophages. J Biol Chem 278, 38437-38442.
[21]Brachmann, S.M., Ueki, K., Engelman, J.A., Kahn, R.C. and Cantley, L.C. (2005). Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol Cell Biol 25,1596-1607.
[22]Okkenhaug, K. et al. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297,1031-1034.
[23]Gukovsky,I. et al. (2004). Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gastroenterology 126, 554-566.
[24]Wymann, M.P., Zvelebil, M. and Laffargue, M. (2003). Phosphoinositide 3-kinase signalling--which way to target? Trends Pharmacol Sci 24,366-376.
[25]Ward, S.G. and Finan, P. (2003). Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Current Opinion in Pharmacology 3,426-434.
[26]Stephens, L.R., Jackson, T.R. and Hawkins, P.T. (1993). Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate:a new intracellular signalling system? Biochim Biophys Acta 1179,27-75.
[27]Hennessy, B.T., Smith, D.L., Ram, P.T., Lu, Y. and Mills, G.B. (2005). Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Disco 4,988-1004.
[28]Oudit, G.Y., Sun, H., Kerfant, B.G., Crackower, M.A., Penninger, J.M. and Backx, P.H. (2004). The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37,449-471.
[29]Falasca, M. and Maffucci, T. (2007). Role of class II phosphoinositide 3-kinase in cell signalling. Biochem Soc Trans 35,211-214.
[30]Herman, P.K., Stack, J.H. and Emr, S.D. (1992). An essential role for a protein and lipid kinase complex in secretory protein sorting. Trends Cell Biol 2,363-368.
[31]Schu, P.V., Takegawa, K., Fry, M.J., Stack, J.H., Waterfield, M.D. and Emr, S.D. (1993). Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260,88-91.
[32]Qu, X. et al. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112,1809-1820.
[33]Yue, Z., Jin, S., Yang, C., Levine, A.J. and Heintz, N. (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100,15077-15082.
[34]Marone, R., Cmiljanovic, V., Giese, B. and Wymann, M.P. (2008). Targeting phosphoinositide 3-kinase:moving towards therapy. Biochim Biophys Acta 1784, 159-185.
[35]Staal, S.P. (1987). Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2:amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A 84,5034-5037.
[36]Bottomley. M.J., Salim, K. and Panayotou, G. (1998). Phospholipid-binding protein domains. Biochim Biophys Acta 1436,165-183.
[37]Fruman, D.A., Rameh, L.E. and Cantley, L.C. (1999). Phosphoinositide binding domains: embracing 3-phosphate. Cell 97,817-820.
[38]Rameh, L.E. and Cantley, L.C. (1999). The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 274,8347-8350.
[39]Sarbassov, D.D., Guertin, D.A., Ali, S.M. and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307,1098-1101.
[40]Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M. and Hemmings, B.A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378,785-789.
[41]Lawlor, M.A. and Alessi, D.R. (2001). PKB/Akt:a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114,2903-2910.
[42]Blume-Jensen, P. and Hunter, T. (2001). Oncogenic kinase signalling. Nature 411,355-65.
[43]Diehl, J.A., Cheng, M., Roussel, M.F. and Sherr, C.J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12, 3499-3511.
[44]Liang, J. et al. (2002). PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8,1153-1160.
[45]Testa, J.R. and Bellacosa, A. (2001). AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 98,10983-10985.
[46]Nave, B.T., Ouwens, M., Withers, D.J., Alessi, D.R. and Shepherd, P.R. (1999). Mammalian target of rapamycin is a direct target for protein kinase B:identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 2,427-431.
[47]Sekulic, A., Hudson, C.C., Homme, J.L., Yin, P., Otterness, D.M., Karnitz, L.M. and Abraham, R.T. (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60.3504-3513.
[48]McManus, E.J. and Alessi, D.R. (2002). TSC1-TSC2:a complex tale of PKB-mediated S6K regulation. Nat Cell Biol 4,214-216.
[49]Osaki, M., Oshimura, M. and Ito, H. (2004). PI3K-Akt pathway:its functions and alterations in human cancer. Apoptosis 9,667-676.
[50]Shin, I., Yakes, F.M., Rojo, F., Shin, N.Y., Bakin, A.V., Baselga, J. and Arteaga, C.L. (?)02). PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kipl) at threonine 157 and modulation of its cellular localization. Nat Med 8,1145-1152.
[51]Viglietto, G. et al. (2002). Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kipl) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8,1136-1144.
[52]Zhou, B.P., Liao, Y., Xia, W., Spohn, B., Lee, M.H. and Hung, M.C. (2001). Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3,245-252.
[53]Guertin, D.A. and Sabatini, D.M. (2007). Defining the role of mTOR in cancer. Cancer Cell 12,9-22.
[54]Sabatini. D.M. (2006). mTOR and cancer:insights into a complex relationship. Nat Rev Cancer 6,729-734.
[55]Guertin, D.A. and Sabatini, D.M. (2005). An expanding role for mTOR in cancer. Trends Mol Med 11,353-361.
[56]Shayesteh, L. et al. (1999). PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genetics 21,99-102.
[57]Zhang, A., Maner, S., Betz, R., Angstrom. T., Stendahl, U., Bergman, F., Zetterberg, A. and Wallin, K.L. (2002). Genetic alterations in cervical carcinomas:Frequent low-level amplifications of oncogenes are associated with human papillomavirus infection. Int J Cancer 101,427-433.
[58]Philp, A.J., Campbell, I.G., Leet, C., Vincan, E., Rockman, S.P., Whitehead, R.H., Thomas, R.J. and Phillips, W.A. (2001). The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61,7426-7429.
[59]Jucker, M., Sudel, K., Horn, S., Sickel, M., Wegner, W., Fiedler, W. and Feldman, R.A. (2002). Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 16,894-901.
[60]Bader, A.G., Kang, S., Zhao, L. and Vogt, P.K. (2005). Oncogenic P13K deregulates transcription and translation. Nat Rev Cancer 5,921-929.
[61]Samuels, Y. and Ericson, K. (2006). Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18,77-82.
[62]Samuels, Y. et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304,554.
[63]Burgering, B.M. and Medema, R.H. (2003). Decisions on life and death:FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 73, 689-701.
[64]Datta, S.R., Brunet, A. and Greenberg, M.E. (1999). Cellular survival:a play in three Akts. Genes Dev 13,2905-2927.
[65]Kennedy, S.G., Kandel, E.S., Cross, T.K. and Hay, N. (1999). Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 19.5800-5810.
[66]Gagnon, V., St-Germain, M.E., Parent, S. and Asselin, E. (2003). Akt activity in endometrial cancer cells:regulation of cell survival through cIAP-1. Int J Oncol 23, 803-810.
[67]Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M. and Donner, D.B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401,82-85.
[68]Romashkova, J.A. and Makarov, S.S. (1999). NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401,86-90.
[69]Mayo, L.D. and Donner, D.B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98,11598-11603.
[70]Zhou, B.P., Liao, Y., Xia, W., Zou, Y., Spohn, B. and Hung, M.C. (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3, 973-982.
[71]Schmitt, C.A. (2003). Senescence, apoptosis and therapy--cutting the lifelines of cancer. Nat Rev Cancer 3,286-295.
[72]Kurose, K., Gilley, K., Matsumoto, S., Watson, P.H., Zhou, X.P. and Eng, C. (2002). Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32,355-357.
[73]Barnes, D.M. and Gillett, C.E. (1998). Cyclin D1 in breast cancer. Breast Cancer Res Treat 52,1-15.
[74]Pelengaris, S., Khan, M. and Evan, G. (2002). c-MYC:more than just a matter of life and death. Nat Rev Cancer 2,764-776.
[75]Sherr, C.J. and Roberts, J.M. (1999). CDK inhibitors:positive and negative regulators of G1-phase progression. Genes Dev 13,1501-1512.
[76]Bellacosa, A. et al. (1995). Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64,280-285.
[77]Cheng, J.Q., Ruggeri, B., Klein, W.M., Sonoda, G., Altomare, D.A., Watson, D.K. and Testa, J.R. (1996). Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 93, 3636-3641.
[78]Ruggeri, B.A., Huang, L., Wood, M., Cheng, J.Q. and Testa, J.R. (1998). Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 21,81-86.
[79]Alkan, S. and lzban, K.F. (2002). Immunohistochemical localization of phosphorylated AKT in multiple myeloma. Blood 99,2278-2279.
[80]Choe, G. et al. (2003). Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63,2742-2746.
[81]Dai, D.L., Martinka, M. and Li, G. (2005). Prognostic significance of activated Akt expression in melanoma:a clinicopathologic study of 292 cases. J Clin Oncol 23, 1473-1482.
[82]Terakawa, N., Kanamori, Y. and Yoshida, S. (2003). Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer 10,203-208.
[83]Yuan. Z.Q. et al. (2000). Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 19,2324-2330.
[84]Schlieman, M.G., Fahy, B.N., Ramsamooj, R., Beckett, L. and Bold, R.J. (2003). Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J cancer 89,2110-2115.
[85]Yamamoto, S. et al. (2004). Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 10,2846-2850.
[86]Nakanishi, K., Sakamoto, M., Yamasaki, S., Todo, S. and Hirohashi, S. (2005). Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer 103,307-312.
[87]Nam, S.Y., Lee, H.S., Jung, G.A., Choi, J., Cho, S.J., Kim, M.K., Kim, W.H. and Lee, B.L. (2003). Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. Apmis 111,1105-1113.
[88]Tsurutani, J., Fukuoka, J., Tsurutani, H., Shih, J.H., Hewitt, S.M., Travis, W.D., Jen, J. and Dennis, P.A. (2006). Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. J Clin Oncol 24, 306-314.
[89]Brognard, J., Clark, A.S., Ni, Y. and Dennis, P.A. (2001). Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61,3986-3997.
[90]Clark, A.S., West, K., Streicher, S. and Dennis, P.A. (2002). Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1,707-717.
[91]Tanno, S. et al. (2004). Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res 64,3486-3490.
[92]Aveyard, J.S., Skilleter, A., Habuchi, T. and Knowles, M.A. (1999). Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80,904-908.
[93]Dahia, P.L. (2000). PTEN, a unique tumor suppressor gene. Endocr Relat Cancer 7, 115-129.
[94]Li, J. et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275,1943-1947.
[95]Rasheed, B.K., Stenzel, T.T., McLendon, R.E., Parsons, R., Friedman, A.H., Friedman, H.S., Bigner, D.D. and Bigner, S.H. (1997). PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57,4187-4190. Bertram, J. et al. (2006). Loss of PTEN is associated with progression to androgen independence. Prostate 66,895-902.
[97]Perez-Tenorio, G., Alkhori, L., Olsson, B., Waltersson, M.A., Nordenskjold, B., Rutqvist, L.E., Skoog, L. and Stal, O. (2007). PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13,3577-3584.
[98]Saal, L.H. et al. (2007). Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A 104,7564-7569.
[99]Yoshimoto, M., Cunha, I.W., Coudry, R.A., Fonseca, F.P., Torres, C.H., Soares. F.A. and Squire, J.A. (2007). FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 97,678-685.
[100]Balsara, B.R., Pei, J., Mitsuuchi, Y., Page, R., Klein-Szanto, A., Wang, H., Unger, M. and Testa, J.R. (2004). Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25,2053-2059.
[101]Powis, G. et al. (1994). Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54,2419-2423.
[102]Schultz, R.M. et al. (1995). In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 15,1135-1139.
[103]Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. and Waterfield, M.D. (2001). Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17,615-675.
[104]Lemke, L.E., Paine-Murrieta, G.D., Taylor, C.W. and Powis, G. (1999). Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase. Cancer Chemother Pharmacol 44. 491-497.
[105]Sanchez-Margalet, V., Goldfine, I.D., Vlahos, C.J. and Sung, C.K. (1994). Role of phosphatidylinositol-3-kinase in insulin receptor signaling:studies with inhibitor, LY294002. Biochem Biophys Res Commun 204,446-452.
[106]Takeda, A., Osaki, M., Adachi, K., Honjo, S. and Ito, H. (2004). Role of the phosphatidylinositol 3'-kinase-Akt signal pathway in the proliferation of human pancreatic ductal carcinoma cell lines. Pancreas 28,353-358.
[107]Semba, S., Itoh, N., Ito, M., Harada, M. and Yamakawa, M. (2002). The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3'-kinase, in human colon cancer cells. Clin Cancer Res 8, 1957-1963.
[108]Asselin, E., Mills, G.B. and Tsang, B.K. (2001). XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res 61,1862-1868.
[109]Edwards, E., Geng, L., Tan, J., Onishko, H., Donnelly, E. and Hallahan, D.E. (2002). Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 62,4671-4677.
[110]Hu, L., Hofmann, J., Lu, Y., Mills, G.B. and Jaffe, R.B. (2002). Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62,1087-1092.
[111]Kim, S.H., Um, J.H., Dong-Won, B., Kwon, B.H., Kim, D.W., Chung, B.S. and Kang, C.D. (2000). Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin. Leuk Res 24,917-925.
[112]Klejman, A., Rushen, L., Morrione, A., Slupianek, A. and Skorski, T. (2002). Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21,5868-5876.
[113]Rozen, F., Edery, I., Meerovitch, K., Dever, T.E.. Merrick, W.C. and Sonenberg. N. (1990). Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol Cell Biol 10,1134-1144.
[114]Sarkaria. J.N., Tibbetts. R.S., Busby, E.C., Kennedy, A.P.. Hill, D.E. and Abraham, R.T. (1998). Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 58,4375-4382.
[115]Wang, Q., Li, N., Wang, X., Kim, M.M. and Evers, B.M. (2002). Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3'-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res 8,1940-1947.
[116]Crul, M. et al. (2002). Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 38,1615-21.
[117]Kondapaka, S.B., Singh, S.S., Dasmahapatra, G.P., Sausville, E.A. and Roy, K.K. (2003). Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2,1093-1103.
[118]Hideshima, T. et al. (2006). Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107,4053-4062.
[119]Momota, H., Nerio, E. and Holland, E.C. (2005). Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65,7429-7435.
[120]Nyakem, M., Cappellini, A., Mantovani, I. and Martelli, A.M. (2006). Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol Cancer Ther 5,1559-1570.
[121]Caron, R.W. et al. (2005). Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther 4.257-270.
[122]Ruiter, G.A., Zerp, S.F., Bartelink, H., van Blitterswijk, W.J. and Verheij, M. (1999). Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 59,2457-2463.
[123]Vink, S.R. et al. (2006). Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol 80, 207-213.
[124]Gills, J.J. et al. (2007). Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and-dependent mechanisms. J Biol Chem 282.27020-27029.
[125]Gills, J.J., Holbeck, S., Hollingshead, M., Hewitt, S.M., Kozikowski, A.P. and Dennis, P.A. (2006). Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther 5,713-722.
[126]Martelli, A.M. et al. (2003). A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. Leukemia 17,1794-1805.
[127]Tabellini, G., Tazzari, P.L., Bortul, R., Billi, A.M., Conte, R., Manzoli, L., Cocco, L. and Martelli, A.M. (2004). Novel 2'-substituted,3'-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway. Br J Haematol 126,574-582.
[128]Van Meter, T.E., Broaddus, W.C., Cash, D. and Fillmore, H. (2006). Cotreatment with a novel phosphoinositide analogue inhibitor and carmustine enhances chemotherapeutic efficacy by attenuating AKT activity in gliomas. Cancer 107,2446-2454.
[129]Chen, J., Ramos, J., Sirisawad, M., Miller, R. and Naumovski, L. (2005). Motexafin gadolinium induces mitochondrially-mediated caspase-dependent apoptosis. Apoptosis 10, 1131-1142.
[130]Puduvalli, V.K., Sampath, D., Bruner, J.M., Nangia, J., Xu, R. and Kyritsis. A.P. (2005). TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation. Apoptosis 10,233-243.
[131]Douros. J. and Suffness, M. (1981). New antitumor substances of natural origin. Cancer Treat Rev 8,63-87.
[132]Eng, C.P., Sehgal, S.N. and Vezina, C. (1984). Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37,1231-1237.
[133]Houchens. D.P., Ovejera, A.A., Riblet, S.M. and Slagel, D.E. (1983). Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 19,799-805.
[134]Marimpietri. D. et al. (2007). Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis. Clin Cancer Res 13, 3977-3988.
[135]Marimpietri, D., Nico, B., Vacca, A., Mangieri, D., Catarsi, P., Ponzoni, M. and Ribatti, D. (2005). Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin. Oncogene 24,6785-6795.
[136]Ribatti, D., Nico, B., Mangieri, D., Longo, V., Sansonno, D., Vacca, A. and Dammacco, F. (2007). In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin. Histol Histopathol 22,285-289.
[137]Haritunians, T., Mori, A., O'Kelly, J., Luong, Q.T., Giles, F.J. and Koeffler, H.P. (2007). Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 21,333-339.
[138]Wanner, K., Hipp, S., Oelsner, M., Ringshausen, I., Bogner, C., Peschel, C. and Decker, T. (2006). Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134,475-484.
[139]Boulay, A., Rudloff, J., Ye, J., Zumstein-Mecker, S., O'Reilly, T., Evans, D.B., Chen, S. and Lane, H.A. (2005). Dual Inhibition of mTOR and Estrogen Receptor Signaling In vitro Induces Cell Death in Models of Breast Cancer. Clinical Cancer Research 11, 5319-5328.
[140]Treeck, O., Wackwitz, B., Haus, U. and Ortmann, O. (2006). Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol Oncol 102,292-299.
[141]Geoerger, B., Kerr, K., Tang, C.B., Fung, K.M., Powell, B., Sutton, L.N., Phillips, P.C. and Janss, A.J. (2001). Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61,1527-1532.
[142]Ito, D., Fujimoto, K., Mori, T., Kami, K., Koizumi, M., Toyoda, E., Kawaguchi, Y. and Doi, R. (2006). In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer 118,2337-2343.
[143]Thallinger, C., Poeppl, W., Pratscher, B., Mayerhofer, M., Valent, P.. Tappeiner, G. and Joukhadar. C. (2007). CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model. Pharmacology 79,207-213.
[144]Thallinger, C., Werzowa, J., Poeppl, W., Kovar, F.M., Pratscher, B., Valent, P., Quehenberger, P. and Joukhadar, C. (2007). Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. J Invest Dermatol 127,2411-1417.
[145]Wu, C., Wangpaichitr, M., Feun, L., Kuo, M.T., Robles, C., Lampidis, T. and Savaraj, N. (2005). Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 4, 1-10.
[146]Albert, J.M., Kim, K.W., Cao, C. and Lu, B. (2006). Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5, 1183-1189.
[147]Kim, K.W., Mutter, R.W., Cao, C., Albert, J.M., Freeman, M., Hallahan, D.E. and Lu, B. (2006). Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. J Biol Chem 281,36883-36890.
[148]Moretti, L., Yang, E.S., Kim, K.W. and Lu, B. (2007). Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat 10, 135-143.
[149]Paglin, S. et al. (2005). Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 65, 11061-11070.
[150]Cao, C., Subhawong, T., Albert, J.M., Kim, K.W., Geng, L., Sekhar, K.R., Gi, Y.J. and Lu, B. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66, 10040-10047.
[151]Shinohara, E.T., Cao, C., Niermann, K., Mu, Y., Zeng, F., Hallahan, D.E. and Lu, B. (2005). Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24,5414-5422.
[152]Chan, S. et al. (2005). Phase Ⅱ study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23,5314-5322.
[153]Chang, S.M. et al. (2005). Phase Ⅱ study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23,357-361.
[154]Galanis, E. et al. (2005). Phase Ⅱ trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme:a North Central Cancer Treatment Group Study. J Clin Oncol 23,5294-5304.
[155]Duran, I. et al. (2006). A phase Ⅱ clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95,1148-1154.
[156]Atkins, M.B. et al. (2004). Randomized phase Ⅱ study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22,909-918.
[157]Witzig, T.E. et al. (2005). Phase Ⅱ trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23,5347-5356.
[158]Yee, K.W. et al. (2006). Phase Ⅰ/Ⅱ study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12,5165-5173.
[159]Rossomando, A.J., Sanghera, J.S., Marsden, L.A., Weber, M.J., Pelech, S.L. and Sturgill, T.W. (1991). Biochemical characterization of a family of serine/threonine protein kinases regulated by tyrosine and serine/threonine phosphorylations. J Biol Chem 266, 20270-20275.
[160]Colicelli, J. (2004). Human RAS superfamily proteins and related GTPases. Sci STKE
[161]Wennerberg, K., Rossman, K.L. and Der, C.J. (2005). The Ras superfamily at a glance. J Cell Sci 118,843-846.
[162]Campbell, S.L., Khosravi-Far, R., Rossman, K.L., Clark, G.J. and Der, C.J. (1998). Increasing complexity of Ras signaling. Oncogene 17.1395-1413.
[163]Cullen, P.J. and Lockyer, P.J. (2002). Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol 3,339-348.
[164]Reuther, G.W. and Der, C.J. (2000). The Ras branch of small GTPases:Ras family members don't fall far from the tree. Curr Opin Cell Biol 12,157-165.
[165]Takai. Y., Sasaki. T. and Matozaki, T. (2001). Small GTP-binding proteins. Physiol Rev 81,153-208.
[166]Lowy, D.R. and Willumsen, B.M. (1993). Function and regulation of ras. Annu Rev Biochem 62,851-891.
[167]Johnson, L. et al. (1997). K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11,2468-3277.
[168]Cox, A.D. and Der, C.J. (1997). Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1333,51-71.
[169]Hancock, J.F., Paterson, H. and Marshall, C.J. (1990). A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63,133-139.
[170]Seabra, M.C. (1998). Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal 10,167-172.
[171]Daub, H., Weiss, F.U., Wallasch, C. and Ullrich, A. (1996). Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379,557-560.
[172]Leevers, S.J., Paterson, H.F. and Marshall, C.J. (1994). Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369,411-414.
[173]Marais, R., Light, Y., Paterson, H.F. and Marshall, C.J. (1995). Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. Embo J 14,3136-3145.
[174]Steelman, L.S., Pohnert, S.C., Shelton, J.G., Franklin, R.A., Bertrand, F.E. and McCubrey, J.A. (2004). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18,189-218.
[175]Nakano, H., Shindo, M., Sakon, S., Nishinaka, S., Mihara, M., Yagita, H. and Okumura, K. (1998). Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci U S A 95,3537-3542.
[176]Zhao, Q. and Lee, F.S. (1999). Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. J Biol Chem 274,8355-8358.
[177]Pouyssegur, J., Volmat, V. and Lenormand, P. (2002). Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem Pharmacol 64,755-763.
[178]Flotho. C. et al. (1999). RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13,32-37.
[179]Stirewalt, D.L., Kopecky, K.J., Meshinchi, S., Appelbaum, F.R., Slovak, M.L., Willman, C.L. and Radich, J.P. (2001). FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97,3589-3595.
[180]Shields, J.M., Pruitt, K., McFall, A., Shaub, A. and Der, C.J. (2000). Understanding Ras: 'it ain't over'til it's over'. Trends Cell Biol 10,147-154.
[181]Cichowski, K., Shih, T.S. and Jacks, T. (1996). Nfl gene targeting:toward models and mechanisms. Semin Cancer Biol 7,291-298.
[182]Garnett, M.J. and Marais, R. (2004). Guilty as charged:B-RAF is a human oncogene. Cancer Cell 6,313-319.
[183]Davidson, B., Givant-Horwitz, V., Lazarovici, P., Risberg, B., Nesland, J.M., Trope, C.G., Schaefer, E. and Reich, R. (2003). Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK):co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis 20, 621-631.
[184]李延, 王滟,杨业洲等。Erk信号转导通路蛋白在上皮性卵巢肿瘤组织中的表达及与肿瘤恶性程度的相关性研究。实用妇产科杂志,2006,22：164-166.
[185]叶丽虹, 尤嘉琮,乔玲等。应用基因表达谱芯片从不同转移能力的乳腺癌细胞中筛选转移相关基因。生物化学与生物物理进展,2005,32：421-428。
[186]Schuierer, M.M., Bataille, F., Weiss, T.S., Hellerbrand, C. and Bosserhoff, A.K. (2006). Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 16, 451-456.
[187]Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J. and Saltiel, A.R. (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92, 7686-7689.
[188]Favata, M.F. et al. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273,18623-18632.
[189]Sebolt-Leopold, J.S. and Herrera, R. (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4,937-947.
[190]Boucher, M.J., Morisset,J., Vachon, P.H., Reed, J.C., Laine, J. and Rivard, N. (2000). MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79,355-369.
[191]Murphy, L.O. et al. (2001). Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions. Br J Cancer 84,926-935.
[192]Xing, C. and Imagawa, W. (1999). Altered MAP kinase (ERK1,2) regulation in primary cultures of mammary tumor cells:elevated basal activity and sustained response to EGF. Carcinogenesis 20,1201-1208.
[193]Duncia, J.V. et al. (1998). MEK inhibitors:the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8,2839-2844.
[194]Sebolt-Leopold, J.S. et al. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5,810-816.
[195]Lorusso, P.M. et al. (2005). Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23,5281-5293.
[196]Yeh, T.C. et al. (2007). Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13, 1576-1583.
[197]Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. and Pandolfi, P.P. (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121,179-193.
[198]Montaner, S., Sodhi, A., Pece, S., Mesri, E.A. and Gutkind, J.S. (2001) The Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Promotes Endothelial Cell Survival through the Activation of Akt/Protein Kinase. Cancer Res 61,2641-2648.
[199]Wang, X. et al. (2007). Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol Cell Biol 27,7405-7413.
[200]Wohlbold, L., van der Kuip, H., Miething, C., Vornlocher, H.P., Knabbe, C., Duyster, J. and Aulitzky, W.E. (2003). Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 102,2236-2239.
[201]Fan, Q.W., Cheng, C.K., Nicolaides, T.P., Hackett, C.S., Knight, Z.A., Shokat. K.M. and Weiss, W.A. (2007). A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67,7960-7965.
[202]Fan, Q.W., Knight, Z.A., Goldenberg, D.D., Yu, W., Mostov, K.E., Stokoe, D., Shokat, K.M. and Weiss, W.A. (2006). A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9,341-349.
[203]Knight, Z.A. et al. (2006). A Pharmacological Map of the PI3-K Family Defines a Role for p110[alpha] in Insulin Signaling. Cell 125,733-747.
[204]Kojima, K. et al. (2008). The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22,1728-1736.
[205]Park, S. et al. (2008). PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22,1698-1706.
[206]Chaisuparat, R., Hu, J., Jham, B.C., Knight, Z.A., Shokat, K.M. and Montaner, S. (2008). Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res 68,8361-8368.
[207]Chen, J.S. et al. (2008). Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7,841-850.
[208]Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E. and Thun, M.J. (2003). Cancer Statistics,2003. CA Cancer J Clin 53,5-26.
[209]Haeder, M., Rotsch, M., Bepler, G., Hennig, C., Havemann, K., Heimann, B. and Moelling, K. (1988). Epidermal growth factor receptor expression in human lung cancer cell lines. Cancer Res 48,1132-1136.
[210]Nicholson, R.I., Gee, J.M. and Harper, M.E. (2001). EGFR and cancer prognosis. Eur J Cancer 37 Suppl 4,9-15.
[211]Ohsaki, Y. et al. (2000). Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7, 603-607.
[212]Lynch, T.J. et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350, 2129-2139.
[213]Paez, J.G. et al. (2004). EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science 304,1497-1500.
[214]Pao, W. et al. (2004). EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101,13306-13311.
[215]Massion, P.P. et al. (2004). Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med 170,1088-1094.
[216]Tsurutani, J. et al. (2007). Prognostic significance of clinical factors and Akt activation in patients with bronchioloalveolar carcinoma. Lung Cancer 55,115-121.
[217]Mitsudomi, T. et al. (1991). ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 51, 4999-5002.
[218]Rodenhuis, S., van de Wetering, M.L., Mooi, W.J., Evers, S.G., van Zandwijk, N. and Bos, J.L. (1987). Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 317,929-935.
[219]Singh, R.P., Agarwal, C. and Agarwal, R. (2003). Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells:modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis 24, 555-563.
[220]Galea, C.A., Wang, Y., Sivakolundu, S.G. and Kriwacki, R.W. (2008). Regulation of cell division by intrinsically unstructured proteins:intrinsic flexibility, modularity, and signaling conduits. Biochemistry 47,7598-7609.
[221]Burkhard, S.J. and Traugh, J.A. (1983). Changes in Ribosome Function by Camp-Dependent and Camp-Independent Phosphorylation of Ribosomal Protein-S6. J Biol Chem 258,4003-4008.
[222]Thomas, G., Siegmann, M. and Gordon, J. (1979). Multiple phosphorylation of ribosomal protein S6 during transition of quiescent 3T3 cells into early G1, and cellular compartmentalization of the phosphate donor. Proc Natl Acad Sci U S A 76,3952-3956.
[223]Roux, P.P., Shahbazian, D., Vu, H., Holz, M.K., Cohen, M.S., Taunton, J.. Sonenberg, N. and Blenis, J. (2007). RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282, 14056-14064.
[224]Shahbazian, D. et al. (2006). The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. Embo J 25,2781-2791.
[225]Chou, T.C. and Talalay, P. (1984). Quantitative analysis of dose-effect relationships:the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22,27-55.
[226]Janmaat, M.L., Rodriguez, J.A., Gallegos-Ruiz, M., Kruyt, F.A. and Giaccone, G. (2006). Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer 118,209-214.
[227]Sun, S.Y., Rosenberg, L.M., Wang, X.R., Zhou, Z.M., Yue, P., Fu, H. and Khuri, F.R. (2005). Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Research 65,7052-7058.
[228]Holz, M.K., Ballif, B.A., Gygi, S.P. and Blenis, J. (2005). mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123,569-580.
[229]Buck, E. et al. (2006). Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Thera 5,2676-2684.
[230]Whyte, D.B. and Holbeck, S.L. (2006). Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Commun 340, 469-475.
[231]Sharma, S.V. et al. (2006). A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10,425-435.
[232]Sharma, S.V., Fischbach, M.A., Haber, D.A. and Settleman, J. (2006). "Oncogenic shock": explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 12, 4392-4395.
[233]Park, S. et al. (2007). PI-103. a dual inhibitor of class I phosphatidylinositide 3-kinase and mTOR. has anti-leukemic activity in acute myeloid leukemia. Blood 110,1-10.
[234]Fan, Q.-W., Cheng, C.K., Nicolaides, T.P., Hackett, C.S., Knight, Z.A., Shokat, K.M. and Weiss, W.A. (2007). A Dual Phosphoinositide-3-Kinase{alpha}/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma. Cancer Res 67,7960-7965.
[235]Legrier, M.E., Yang, C.P., Yan, H.G., Lopez-Barcons, L., Keller, S.M., Perez-Soler, R., Horwitz, S.B. and McDaid, H.M. (2007). Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 67,11300-11308.
[236]Chun, P.Y., Feng, F.Y., Scheurer, A.M., Davis, M.A, Lawrence, T.S. and Nyati, M.K. (2006). Synergistic effects of gemcitabine and gefitinib in the treatment of head and neck carcinoma. Cancer Res 66,981-988.
[237]Nakamura, H., Takamori, S., Fujii, T., Ono, M., Yamana, H., Kuwano, M. and Shirouzu, K. (2005). Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. Cancer Lett 230, 33-46.
[238]Molhoek, K.R., Brautigan, D.L. and Slingluff, C.L., Jr. (2005). Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J Transl Med 3,39-50.
[239]Maione, P., Gridelli, C., Troiani, T. and Ciardiello, F. (2006). Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist 11, 274-284.
[240]于小云。紫杉醇加顺铂治疗晚期非小细胞肺癌的临床观察。现代中西医结合杂志,2008,17：5130-5130.
[241]张燕 和 董建红。紫杉醇抗肿瘤作用机制研究现状。现代中西医结合杂志,2005,14：3312-3313。
[242]Sumitomo, M., Asano, T., Asakuma, J., Asano, T., Horiguchi, A. and Hayakawa, M. (2004). ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin Cancer Res 10,794-801.
[243]Maione, P., Gridelli, C., Troiani, T. and Ciardiello, F. (2006). Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC. The Oncologist 11,274-284.
[244]Hu, Y., Bally, M., Dragowska, W.H. and Mayer, L. (2003). Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. Mol Cancer Ther 2,641-649.
[245]McDaid, H.M., Lopez-Barcons, L., Grossman, A., Lia, M., Keller, S., Perez-Soler, R. and Horwitz, S.B. (2005). Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res 65,2854-2860.
[246]Nguyen, D.M., Chen, G.A., Reddy, R., Tsai, W., Schrump, W.D., Cole, G., Jr. and Schrump, D.S. (2004). Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway. J Thorac Cardiovasc Surg 127,365-375.
[247]Philipp-Staheli, J., Kim, K.H., Liggitt, D., Gurley, K.E., Longton, G. and Kemp, C.J. (2004). Distinct roles for p53, p27Kipl, and p21Cipl during tumor development. Oncogene 23,905-913.
[248]Danial, N.N. et al. (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424,952-956.
[249]Han, E.K., Gehrke, L., Tahir, S.K., Credo, R.B., Cherian, S.P., Sham, H., Rosenberg, S.H. and Ng, S. (2000). Modulation of drug resistance by alpha-tubulin in paclitaxel-resistant human lung cancer cell lines. Eur J Cancer 36,1565-1571.
[250]Bacus, S.S. et al. (2001). Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20,147-155.
[251]Kawaguchi, W. et al. (2007). Simultaneous inhibition of the mitogen-activated protein kinase kinase and phosphatidylinositol 3'-kinase pathways enhances sensitivity to paclitaxel in ovarian carcinoma. Cancer Sci 98,2002-2008.
[252]Shi, Y. et al. (2005). Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Neoplasia 7,992-1000.
[253]肖颖 和 赵玉斌。红豆杉中紫杉醇抗癌研究进展。现代中西医结合杂志,2008,17：5557-5558。
[254]施亚军。晚期结肠癌分子靶向治疗的研究进展。现代中西医结合杂志,2007,16：1145-1147.
[255]Hurwitz, H. et al. (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350,2335-2342.
[256]Hollywood, E. (2002). Clinical issues in the administration of an anti-epidermal growth factor receptor monoclonal antibody, IMC-C225. Semin Oncol Nurs 18,30-35.
[257]Loeffler-Ragg, J., Skvortsov, S., Sarg, B., Skvortsova, I., Witsch-Baumgartner, M., Mueller, D., Lindner, H. and Zwierzina, H. (2005). Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines. Eur J Cancer 41,2338-2346.
[258]叶胜龙。关注原发性肝癌的靶向治疗研究。中华肝脏病杂志,20005,13：322-323。
[259]Sutter, A.P., Hopfner, M., Huether, A., Maaser, K. and Scherubl, H. (2006). Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer. Int J Cancer 118,1814-1822.
[260]Zhang, X., Gaspard, J.P. and Chung, D.C. (2001). Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res 61, 6050-6054.
[261]Yu, C., Friday, B.B., Lai, J.P., McCollum, A., Atadja, P., Roberts, L.R. and Adjei, A.A. (2007). Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin Cancer Res 13,1140-1148.
[262]Dai, Y., Rahmani, M., Pei, X.Y., Khanna, P., Han, S.I., Mitchell, C., Dent, P. and Grant, S. (2005). Farnesyltransferase inhibitors interact synergistically with the Chkl inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 105,1706-1716.
[263]Mukohara. T., Civiello, G., Johnson, B.E. and Janne, P.A. (2005). Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma. Oncology 68,500-510.
[264]Greenhough, A., Patsos, H.A., Williams, A.C. and Paraskeva. C. (2007). The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer 121, 2172-2180.
[265]Guillard, S. et al. (2009). Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 8,443-453.
[266]MacKeigan, J.P., Taxman, D.J., Hunter, D., Earp, H.S.,3rd, Graves, L.M. and Ting, J.P. (2002). Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase kinase inhibition. Clin Cancer Res 8,2091-2099.
[267]Zhu, K. et al. (2005). Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Blood 105,4759-4766.
[268]Mabuchi, S. et al. (2002). Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem 277,33490-33500.
[269]周鸿,山杉公男。Dha对大白鼠血胆固醇浓度及磷脂分子组成的影响.江西科学,2003,21：95-100。
[270]Ding, W.Q. and Lind, S.E. (2007). Phospholipid hydroperoxide glutathione peroxidase plays a role in protecting cancer cells from docosahexaenoic acid-induced cytotoxicity. Mol Cancer Ther 6,1467-1474.
[271]Hardman, W.E. (2007). Dietary canola oil suppressed growth of implanted MDA-MB 231 human breast tumors in nude mice. Nutr Cancer 57,177-183.
[272]Khan, N.A., Nishimura, K., Aires, V., Yamashita, T., Oaxaca-Castillo, D., Kashiwagi, K. and Igarashi, K. (2006). Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation. J Lipid Res 47,2306-2313.
[273]Rose, D.P. and Connolly, J.M. (1999). Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 83,217-244.
[274]Liu, G., Bibus, D.M., Bode, A.M., Ma, W.Y., Holman, R.T. and Dong, Z. (2001). Omega 3
but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci U S A 98,7510-7515.
[275]Brown, M., Bellon, M. and Nicot, C. (2007). Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-1-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1. Blood 109,1653-1659.
[276]王静,糜漫天, 韦娜 和 王斌。不同膳食脂肪酸构成对乳腺癌大鼠brcal表达的影响.实用医药杂志,2007,24：84-86。
[277]Akbar, M., Calderon, F., Wen, Z. and Kim, H.Y. (2005). Docosahexaenoic acid:a positive modulator of Akt signaling in neuronal survival. Proc Natl Acad Sci U S A 102, 10858-10863.
[278]Maheo, K., Vibet, S., Steghens, J.P., Dartigeas, C., Lehman, M., Bougnoux, P. and Gore, J. (2005). Differential sensitization of cancer cells to doxorubicin by DHA:a role for lipoperoxidation. Free Radic Biol Med 39,742-751.
[279]Kishida, E., Tajiri, M. and Masuzawa, Y. (2006). Docosahexaenoic acid enrichement can reduce L929 cell necrosis induced by tumor necrosis factor. Biochim Biophys Acta 1761,454-462.
[2]Fruman, D.A., Meyers, R.E. and Cantley, L.C. (1998). Phosphoinositide kinases. Annu Rev Biochem 67,481-507.
[3]Hiles, I.D. et al. (1992). Phosphatidylinositol 3-kinase:structure and expression of the 110 kd catalytic subunit. Cell 70,419-429.
[4]Jimenez, C. et al. (1998). Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. Embo J 17,743-753.
[5]Pawson, T. and Nash, P. (2000). Protein-protein interactions define specificity in signal transduction. Genes Dev 14,1027-1047.
[6]Macara, I.G., Marinetti, G.V. and Balduzzi, P.C. (1984). Transforming Protein of Avian-Sarcoma Virus Ur2 Is Associated with Phosphatidylinositol Kinase-Activity Possible Role in Tumorigenesis. Proc Natl Acad Sci U S A 81,2728-2732.
[7]Sugimoto, Y., Whitman, M., Cantley, L.C. and Erikson, R.L. (1984). Evidence That the Rous-Sarcoma Virus Transforming Gene-Product Phosphorylates Phosphatidylinositol and Diacylglycerol. Proc Natl Acad Sci U S A 81,2117-2121.
[8]Whitman, M., Kaplan, D.R., Schaffhausen, B., Cantley, L. and Roberts, T.M. (1985). Association of Phosphatidylinositol Kinase-Activity with Polyoma Middle-T Competent for Transformation. Nature 315,239-242.
[9]Vanhaesebroeck, B. et al. (2001). Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70,535-602.
[10]Wymann, M.P. and Pirola, L. (1998). Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1436,127-150.
[11]Vivanco, I. and Sawyers, C.L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2,489-501.
[12]Bi, L., Okabe, I., Bernard, D.J., Wynshaw-Boris, A. and Nussbaum, R.L. (1999). Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 274,10963-10968.
[13]Bilancio, A., Okkenhaug, K., Camps, M., Emery, J.L., Ruckle, T., Rommel, C. and Vanhaesebroeck, B. (2006). Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling:comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107,642-650.
[14]Campbell, M., Allen, W.E., Sawyer, C., Vanhaesebroeck, B. and Trimble, E.R. (2004). Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res 95,380-388.
[15]Condliffe, A.M. et al. (2005). Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106,1432-1440.
[16]Northcott, C.A., Hayflick, J. and Watts, S.W. (2005). Upregulated function of phosphatidylinositol-3-kinase in genetically hypertensive rats:a moderator of arterial hypercontractility. Clin Exp Pharmacol Physiol 32,851-858.
[17]Sujobert, P. et al. (2005). Essential role for the pllOdelta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106, 1063-1066.
[18]Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D.A., Wood, C., Gray, P.W., Cooper, J.A. and Hoekstra, M.F. (1997). p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272,19236-19241.
[19]Jackson, S.P. et al. (2005). PI 3-kinase p110beta:a new target for antithrombotic therapy. Nat Med 11,507-514.
[20]Leverrier, Y., Okkenhaug, K., Sawyer, C., Bilancio, A., Vanhaesebroeck, B. and Ridley, A.J. (2003). Class I phosphoinositide 3-kinase p110beta is required for apoptotic cell and Fcgamma receptor-mediated phagocytosis by macrophages. J Biol Chem 278, 38437-38442.
[21]Brachmann, S.M., Ueki, K., Engelman, J.A., Kahn, R.C. and Cantley, L.C. (2005). Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol Cell Biol 25,1596-1607.
[22]Okkenhaug, K. et al. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297,1031-1034.
[23]Gukovsky,I. et al. (2004). Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gastroenterology 126, 554-566.
[24]Wymann, M.P., Zvelebil, M. and Laffargue, M. (2003). Phosphoinositide 3-kinase signalling--which way to target? Trends Pharmacol Sci 24,366-376.
[25]Ward, S.G. and Finan, P. (2003). Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Current Opinion in Pharmacology 3,426-434.
[26]Stephens, L.R., Jackson, T.R. and Hawkins, P.T. (1993). Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate:a new intracellular signalling system? Biochim Biophys Acta 1179,27-75.
[27]Hennessy, B.T., Smith, D.L., Ram, P.T., Lu, Y. and Mills, G.B. (2005). Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Disco 4,988-1004.
[28]Oudit, G.Y., Sun, H., Kerfant, B.G., Crackower, M.A., Penninger, J.M. and Backx, P.H. (2004). The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37,449-471.
[29]Falasca, M. and Maffucci, T. (2007). Role of class II phosphoinositide 3-kinase in cell signalling. Biochem Soc Trans 35,211-214.
[30]Herman, P.K., Stack, J.H. and Emr, S.D. (1992). An essential role for a protein and lipid kinase complex in secretory protein sorting. Trends Cell Biol 2,363-368.
[31]Schu, P.V., Takegawa, K., Fry, M.J., Stack, J.H., Waterfield, M.D. and Emr, S.D. (1993). Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260,88-91.
[32]Qu, X. et al. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112,1809-1820.
[33]Yue, Z., Jin, S., Yang, C., Levine, A.J. and Heintz, N. (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100,15077-15082.
[34]Marone, R., Cmiljanovic, V., Giese, B. and Wymann, M.P. (2008). Targeting phosphoinositide 3-kinase:moving towards therapy. Biochim Biophys Acta 1784, 159-185.
[35]Staal, S.P. (1987). Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2:amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A 84,5034-5037.
[36]Bottomley. M.J., Salim, K. and Panayotou, G. (1998). Phospholipid-binding protein domains. Biochim Biophys Acta 1436,165-183.
[37]Fruman, D.A., Rameh, L.E. and Cantley, L.C. (1999). Phosphoinositide binding domains: embracing 3-phosphate. Cell 97,817-820.
[38]Rameh, L.E. and Cantley, L.C. (1999). The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 274,8347-8350.
[39]Sarbassov, D.D., Guertin, D.A., Ali, S.M. and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307,1098-1101.
[40]Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M. and Hemmings, B.A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378,785-789.
[41]Lawlor, M.A. and Alessi, D.R. (2001). PKB/Akt:a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114,2903-2910.
[42]Blume-Jensen, P. and Hunter, T. (2001). Oncogenic kinase signalling. Nature 411,355-65.
[43]Diehl, J.A., Cheng, M., Roussel, M.F. and Sherr, C.J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12, 3499-3511.
[44]Liang, J. et al. (2002). PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8,1153-1160.
[45]Testa, J.R. and Bellacosa, A. (2001). AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 98,10983-10985.
[46]Nave, B.T., Ouwens, M., Withers, D.J., Alessi, D.R. and Shepherd, P.R. (1999). Mammalian target of rapamycin is a direct target for protein kinase B:identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 2,427-431.
[47]Sekulic, A., Hudson, C.C., Homme, J.L., Yin, P., Otterness, D.M., Karnitz, L.M. and Abraham, R.T. (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60.3504-3513.
[48]McManus, E.J. and Alessi, D.R. (2002). TSC1-TSC2:a complex tale of PKB-mediated S6K regulation. Nat Cell Biol 4,214-216.
[49]Osaki, M., Oshimura, M. and Ito, H. (2004). PI3K-Akt pathway:its functions and alterations in human cancer. Apoptosis 9,667-676.
[50]Shin, I., Yakes, F.M., Rojo, F., Shin, N.Y., Bakin, A.V., Baselga, J. and Arteaga, C.L. (?)02). PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kipl) at threonine 157 and modulation of its cellular localization. Nat Med 8,1145-1152.
[51]Viglietto, G. et al. (2002). Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kipl) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8,1136-1144.
[52]Zhou, B.P., Liao, Y., Xia, W., Spohn, B., Lee, M.H. and Hung, M.C. (2001). Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3,245-252.
[53]Guertin, D.A. and Sabatini, D.M. (2007). Defining the role of mTOR in cancer. Cancer Cell 12,9-22.
[54]Sabatini. D.M. (2006). mTOR and cancer:insights into a complex relationship. Nat Rev Cancer 6,729-734.
[55]Guertin, D.A. and Sabatini, D.M. (2005). An expanding role for mTOR in cancer. Trends Mol Med 11,353-361.
[56]Shayesteh, L. et al. (1999). PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genetics 21,99-102.
[57]Zhang, A., Maner, S., Betz, R., Angstrom. T., Stendahl, U., Bergman, F., Zetterberg, A. and Wallin, K.L. (2002). Genetic alterations in cervical carcinomas:Frequent low-level amplifications of oncogenes are associated with human papillomavirus infection. Int J Cancer 101,427-433.
[58]Philp, A.J., Campbell, I.G., Leet, C., Vincan, E., Rockman, S.P., Whitehead, R.H., Thomas, R.J. and Phillips, W.A. (2001). The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61,7426-7429.
[59]Jucker, M., Sudel, K., Horn, S., Sickel, M., Wegner, W., Fiedler, W. and Feldman, R.A. (2002). Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 16,894-901.
[60]Bader, A.G., Kang, S., Zhao, L. and Vogt, P.K. (2005). Oncogenic P13K deregulates transcription and translation. Nat Rev Cancer 5,921-929.
[61]Samuels, Y. and Ericson, K. (2006). Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18,77-82.
[62]Samuels, Y. et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304,554.
[63]Burgering, B.M. and Medema, R.H. (2003). Decisions on life and death:FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 73, 689-701.
[64]Datta, S.R., Brunet, A. and Greenberg, M.E. (1999). Cellular survival:a play in three Akts. Genes Dev 13,2905-2927.
[65]Kennedy, S.G., Kandel, E.S., Cross, T.K. and Hay, N. (1999). Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 19.5800-5810.
[66]Gagnon, V., St-Germain, M.E., Parent, S. and Asselin, E. (2003). Akt activity in endometrial cancer cells:regulation of cell survival through cIAP-1. Int J Oncol 23, 803-810.
[67]Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M. and Donner, D.B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401,82-85.
[68]Romashkova, J.A. and Makarov, S.S. (1999). NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401,86-90.
[69]Mayo, L.D. and Donner, D.B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98,11598-11603.
[70]Zhou, B.P., Liao, Y., Xia, W., Zou, Y., Spohn, B. and Hung, M.C. (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3, 973-982.
[71]Schmitt, C.A. (2003). Senescence, apoptosis and therapy--cutting the lifelines of cancer. Nat Rev Cancer 3,286-295.
[72]Kurose, K., Gilley, K., Matsumoto, S., Watson, P.H., Zhou, X.P. and Eng, C. (2002). Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32,355-357.
[73]Barnes, D.M. and Gillett, C.E. (1998). Cyclin D1 in breast cancer. Breast Cancer Res Treat 52,1-15.
[74]Pelengaris, S., Khan, M. and Evan, G. (2002). c-MYC:more than just a matter of life and death. Nat Rev Cancer 2,764-776.
[75]Sherr, C.J. and Roberts, J.M. (1999). CDK inhibitors:positive and negative regulators of G1-phase progression. Genes Dev 13,1501-1512.
[76]Bellacosa, A. et al. (1995). Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64,280-285.
[77]Cheng, J.Q., Ruggeri, B., Klein, W.M., Sonoda, G., Altomare, D.A., Watson, D.K. and Testa, J.R. (1996). Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 93, 3636-3641.
[78]Ruggeri, B.A., Huang, L., Wood, M., Cheng, J.Q. and Testa, J.R. (1998). Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 21,81-86.
[79]Alkan, S. and lzban, K.F. (2002). Immunohistochemical localization of phosphorylated AKT in multiple myeloma. Blood 99,2278-2279.
[80]Choe, G. et al. (2003). Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63,2742-2746.
[81]Dai, D.L., Martinka, M. and Li, G. (2005). Prognostic significance of activated Akt expression in melanoma:a clinicopathologic study of 292 cases. J Clin Oncol 23, 1473-1482.
[82]Terakawa, N., Kanamori, Y. and Yoshida, S. (2003). Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer 10,203-208.
[83]Yuan. Z.Q. et al. (2000). Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 19,2324-2330.
[84]Schlieman, M.G., Fahy, B.N., Ramsamooj, R., Beckett, L. and Bold, R.J. (2003). Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J cancer 89,2110-2115.
[85]Yamamoto, S. et al. (2004). Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 10,2846-2850.
[86]Nakanishi, K., Sakamoto, M., Yamasaki, S., Todo, S. and Hirohashi, S. (2005). Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer 103,307-312.
[87]Nam, S.Y., Lee, H.S., Jung, G.A., Choi, J., Cho, S.J., Kim, M.K., Kim, W.H. and Lee, B.L. (2003). Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. Apmis 111,1105-1113.
[88]Tsurutani, J., Fukuoka, J., Tsurutani, H., Shih, J.H., Hewitt, S.M., Travis, W.D., Jen, J. and Dennis, P.A. (2006). Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. J Clin Oncol 24, 306-314.
[89]Brognard, J., Clark, A.S., Ni, Y. and Dennis, P.A. (2001). Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61,3986-3997.
[90]Clark, A.S., West, K., Streicher, S. and Dennis, P.A. (2002). Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1,707-717.
[91]Tanno, S. et al. (2004). Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res 64,3486-3490.
[92]Aveyard, J.S., Skilleter, A., Habuchi, T. and Knowles, M.A. (1999). Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80,904-908.
[93]Dahia, P.L. (2000). PTEN, a unique tumor suppressor gene. Endocr Relat Cancer 7, 115-129.
[94]Li, J. et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275,1943-1947.
[95]Rasheed, B.K., Stenzel, T.T., McLendon, R.E., Parsons, R., Friedman, A.H., Friedman, H.S., Bigner, D.D. and Bigner, S.H. (1997). PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57,4187-4190. Bertram, J. et al. (2006). Loss of PTEN is associated with progression to androgen independence. Prostate 66,895-902.
[97]Perez-Tenorio, G., Alkhori, L., Olsson, B., Waltersson, M.A., Nordenskjold, B., Rutqvist, L.E., Skoog, L. and Stal, O. (2007). PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13,3577-3584.
[98]Saal, L.H. et al. (2007). Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A 104,7564-7569.
[99]Yoshimoto, M., Cunha, I.W., Coudry, R.A., Fonseca, F.P., Torres, C.H., Soares. F.A. and Squire, J.A. (2007). FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 97,678-685.
[100]Balsara, B.R., Pei, J., Mitsuuchi, Y., Page, R., Klein-Szanto, A., Wang, H., Unger, M. and Testa, J.R. (2004). Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25,2053-2059.
[101]Powis, G. et al. (1994). Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54,2419-2423.
[102]Schultz, R.M. et al. (1995). In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 15,1135-1139.
[103]Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. and Waterfield, M.D. (2001). Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17,615-675.
[104]Lemke, L.E., Paine-Murrieta, G.D., Taylor, C.W. and Powis, G. (1999). Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase. Cancer Chemother Pharmacol 44. 491-497.
[105]Sanchez-Margalet, V., Goldfine, I.D., Vlahos, C.J. and Sung, C.K. (1994). Role of phosphatidylinositol-3-kinase in insulin receptor signaling:studies with inhibitor, LY294002. Biochem Biophys Res Commun 204,446-452.
[106]Takeda, A., Osaki, M., Adachi, K., Honjo, S. and Ito, H. (2004). Role of the phosphatidylinositol 3'-kinase-Akt signal pathway in the proliferation of human pancreatic ductal carcinoma cell lines. Pancreas 28,353-358.
[107]Semba, S., Itoh, N., Ito, M., Harada, M. and Yamakawa, M. (2002). The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3'-kinase, in human colon cancer cells. Clin Cancer Res 8, 1957-1963.
[108]Asselin, E., Mills, G.B. and Tsang, B.K. (2001). XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res 61,1862-1868.
[109]Edwards, E., Geng, L., Tan, J., Onishko, H., Donnelly, E. and Hallahan, D.E. (2002). Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 62,4671-4677.
[110]Hu, L., Hofmann, J., Lu, Y., Mills, G.B. and Jaffe, R.B. (2002). Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62,1087-1092.
[111]Kim, S.H., Um, J.H., Dong-Won, B., Kwon, B.H., Kim, D.W., Chung, B.S. and Kang, C.D. (2000). Potentiation of chemosensitivity in multidrug-resistant human leukemia CEM cells by inhibition of DNA-dependent protein kinase using wortmannin. Leuk Res 24,917-925.
[112]Klejman, A., Rushen, L., Morrione, A., Slupianek, A. and Skorski, T. (2002). Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21,5868-5876.
[113]Rozen, F., Edery, I., Meerovitch, K., Dever, T.E.. Merrick, W.C. and Sonenberg. N. (1990). Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol Cell Biol 10,1134-1144.
[114]Sarkaria. J.N., Tibbetts. R.S., Busby, E.C., Kennedy, A.P.. Hill, D.E. and Abraham, R.T. (1998). Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 58,4375-4382.
[115]Wang, Q., Li, N., Wang, X., Kim, M.M. and Evers, B.M. (2002). Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3'-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res 8,1940-1947.
[116]Crul, M. et al. (2002). Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 38,1615-21.
[117]Kondapaka, S.B., Singh, S.S., Dasmahapatra, G.P., Sausville, E.A. and Roy, K.K. (2003). Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2,1093-1103.
[118]Hideshima, T. et al. (2006). Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107,4053-4062.
[119]Momota, H., Nerio, E. and Holland, E.C. (2005). Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65,7429-7435.
[120]Nyakem, M., Cappellini, A., Mantovani, I. and Martelli, A.M. (2006). Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol Cancer Ther 5,1559-1570.
[121]Caron, R.W. et al. (2005). Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther 4.257-270.
[122]Ruiter, G.A., Zerp, S.F., Bartelink, H., van Blitterswijk, W.J. and Verheij, M. (1999). Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 59,2457-2463.
[123]Vink, S.R. et al. (2006). Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol 80, 207-213.
[124]Gills, J.J. et al. (2007). Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and-dependent mechanisms. J Biol Chem 282.27020-27029.
[125]Gills, J.J., Holbeck, S., Hollingshead, M., Hewitt, S.M., Kozikowski, A.P. and Dennis, P.A. (2006). Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther 5,713-722.
[126]Martelli, A.M. et al. (2003). A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. Leukemia 17,1794-1805.
[127]Tabellini, G., Tazzari, P.L., Bortul, R., Billi, A.M., Conte, R., Manzoli, L., Cocco, L. and Martelli, A.M. (2004). Novel 2'-substituted,3'-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway. Br J Haematol 126,574-582.
[128]Van Meter, T.E., Broaddus, W.C., Cash, D. and Fillmore, H. (2006). Cotreatment with a novel phosphoinositide analogue inhibitor and carmustine enhances chemotherapeutic efficacy by attenuating AKT activity in gliomas. Cancer 107,2446-2454.
[129]Chen, J., Ramos, J., Sirisawad, M., Miller, R. and Naumovski, L. (2005). Motexafin gadolinium induces mitochondrially-mediated caspase-dependent apoptosis. Apoptosis 10, 1131-1142.
[130]Puduvalli, V.K., Sampath, D., Bruner, J.M., Nangia, J., Xu, R. and Kyritsis. A.P. (2005). TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation. Apoptosis 10,233-243.
[131]Douros. J. and Suffness, M. (1981). New antitumor substances of natural origin. Cancer Treat Rev 8,63-87.
[132]Eng, C.P., Sehgal, S.N. and Vezina, C. (1984). Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37,1231-1237.
[133]Houchens. D.P., Ovejera, A.A., Riblet, S.M. and Slagel, D.E. (1983). Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 19,799-805.
[134]Marimpietri. D. et al. (2007). Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis. Clin Cancer Res 13, 3977-3988.
[135]Marimpietri, D., Nico, B., Vacca, A., Mangieri, D., Catarsi, P., Ponzoni, M. and Ribatti, D. (2005). Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin. Oncogene 24,6785-6795.
[136]Ribatti, D., Nico, B., Mangieri, D., Longo, V., Sansonno, D., Vacca, A. and Dammacco, F. (2007). In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin. Histol Histopathol 22,285-289.
[137]Haritunians, T., Mori, A., O'Kelly, J., Luong, Q.T., Giles, F.J. and Koeffler, H.P. (2007). Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 21,333-339.
[138]Wanner, K., Hipp, S., Oelsner, M., Ringshausen, I., Bogner, C., Peschel, C. and Decker, T. (2006). Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134,475-484.
[139]Boulay, A., Rudloff, J., Ye, J., Zumstein-Mecker, S., O'Reilly, T., Evans, D.B., Chen, S. and Lane, H.A. (2005). Dual Inhibition of mTOR and Estrogen Receptor Signaling In vitro Induces Cell Death in Models of Breast Cancer. Clinical Cancer Research 11, 5319-5328.
[140]Treeck, O., Wackwitz, B., Haus, U. and Ortmann, O. (2006). Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol Oncol 102,292-299.
[141]Geoerger, B., Kerr, K., Tang, C.B., Fung, K.M., Powell, B., Sutton, L.N., Phillips, P.C. and Janss, A.J. (2001). Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61,1527-1532.
[142]Ito, D., Fujimoto, K., Mori, T., Kami, K., Koizumi, M., Toyoda, E., Kawaguchi, Y. and Doi, R. (2006). In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer 118,2337-2343.
[143]Thallinger, C., Poeppl, W., Pratscher, B., Mayerhofer, M., Valent, P.. Tappeiner, G. and Joukhadar. C. (2007). CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model. Pharmacology 79,207-213.
[144]Thallinger, C., Werzowa, J., Poeppl, W., Kovar, F.M., Pratscher, B., Valent, P., Quehenberger, P. and Joukhadar, C. (2007). Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. J Invest Dermatol 127,2411-1417.
[145]Wu, C., Wangpaichitr, M., Feun, L., Kuo, M.T., Robles, C., Lampidis, T. and Savaraj, N. (2005). Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 4, 1-10.
[146]Albert, J.M., Kim, K.W., Cao, C. and Lu, B. (2006). Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5, 1183-1189.
[147]Kim, K.W., Mutter, R.W., Cao, C., Albert, J.M., Freeman, M., Hallahan, D.E. and Lu, B. (2006). Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. J Biol Chem 281,36883-36890.
[148]Moretti, L., Yang, E.S., Kim, K.W. and Lu, B. (2007). Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat 10, 135-143.
[149]Paglin, S. et al. (2005). Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 65, 11061-11070.
[150]Cao, C., Subhawong, T., Albert, J.M., Kim, K.W., Geng, L., Sekhar, K.R., Gi, Y.J. and Lu, B. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66, 10040-10047.
[151]Shinohara, E.T., Cao, C., Niermann, K., Mu, Y., Zeng, F., Hallahan, D.E. and Lu, B. (2005). Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24,5414-5422.
[152]Chan, S. et al. (2005). Phase Ⅱ study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23,5314-5322.
[153]Chang, S.M. et al. (2005). Phase Ⅱ study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23,357-361.
[154]Galanis, E. et al. (2005). Phase Ⅱ trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme:a North Central Cancer Treatment Group Study. J Clin Oncol 23,5294-5304.
[155]Duran, I. et al. (2006). A phase Ⅱ clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95,1148-1154.
[156]Atkins, M.B. et al. (2004). Randomized phase Ⅱ study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22,909-918.
[157]Witzig, T.E. et al. (2005). Phase Ⅱ trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23,5347-5356.
[158]Yee, K.W. et al. (2006). Phase Ⅰ/Ⅱ study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12,5165-5173.
[159]Rossomando, A.J., Sanghera, J.S., Marsden, L.A., Weber, M.J., Pelech, S.L. and Sturgill, T.W. (1991). Biochemical characterization of a family of serine/threonine protein kinases regulated by tyrosine and serine/threonine phosphorylations. J Biol Chem 266, 20270-20275.
[160]Colicelli, J. (2004). Human RAS superfamily proteins and related GTPases. Sci STKE
[161]Wennerberg, K., Rossman, K.L. and Der, C.J. (2005). The Ras superfamily at a glance. J Cell Sci 118,843-846.
[162]Campbell, S.L., Khosravi-Far, R., Rossman, K.L., Clark, G.J. and Der, C.J. (1998). Increasing complexity of Ras signaling. Oncogene 17.1395-1413.
[163]Cullen, P.J. and Lockyer, P.J. (2002). Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol 3,339-348.
[164]Reuther, G.W. and Der, C.J. (2000). The Ras branch of small GTPases:Ras family members don't fall far from the tree. Curr Opin Cell Biol 12,157-165.
[165]Takai. Y., Sasaki. T. and Matozaki, T. (2001). Small GTP-binding proteins. Physiol Rev 81,153-208.
[166]Lowy, D.R. and Willumsen, B.M. (1993). Function and regulation of ras. Annu Rev Biochem 62,851-891.
[167]Johnson, L. et al. (1997). K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11,2468-3277.
[168]Cox, A.D. and Der, C.J. (1997). Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1333,51-71.
[169]Hancock, J.F., Paterson, H. and Marshall, C.J. (1990). A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63,133-139.
[170]Seabra, M.C. (1998). Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal 10,167-172.
[171]Daub, H., Weiss, F.U., Wallasch, C. and Ullrich, A. (1996). Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379,557-560.
[172]Leevers, S.J., Paterson, H.F. and Marshall, C.J. (1994). Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369,411-414.
[173]Marais, R., Light, Y., Paterson, H.F. and Marshall, C.J. (1995). Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. Embo J 14,3136-3145.
[174]Steelman, L.S., Pohnert, S.C., Shelton, J.G., Franklin, R.A., Bertrand, F.E. and McCubrey, J.A. (2004). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18,189-218.
[175]Nakano, H., Shindo, M., Sakon, S., Nishinaka, S., Mihara, M., Yagita, H. and Okumura, K. (1998). Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci U S A 95,3537-3542.
[176]Zhao, Q. and Lee, F.S. (1999). Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. J Biol Chem 274,8355-8358.
[177]Pouyssegur, J., Volmat, V. and Lenormand, P. (2002). Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem Pharmacol 64,755-763.
[178]Flotho. C. et al. (1999). RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13,32-37.
[179]Stirewalt, D.L., Kopecky, K.J., Meshinchi, S., Appelbaum, F.R., Slovak, M.L., Willman, C.L. and Radich, J.P. (2001). FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97,3589-3595.
[180]Shields, J.M., Pruitt, K., McFall, A., Shaub, A. and Der, C.J. (2000). Understanding Ras: 'it ain't over'til it's over'. Trends Cell Biol 10,147-154.
[181]Cichowski, K., Shih, T.S. and Jacks, T. (1996). Nfl gene targeting:toward models and mechanisms. Semin Cancer Biol 7,291-298.
[182]Garnett, M.J. and Marais, R. (2004). Guilty as charged:B-RAF is a human oncogene. Cancer Cell 6,313-319.
[183]Davidson, B., Givant-Horwitz, V., Lazarovici, P., Risberg, B., Nesland, J.M., Trope, C.G., Schaefer, E. and Reich, R. (2003). Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK):co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis 20, 621-631.
[184]李延, 王滟,杨业洲等。Erk信号转导通路蛋白在上皮性卵巢肿瘤组织中的表达及与肿瘤恶性程度的相关性研究。实用妇产科杂志,2006,22：164-166.
[185]叶丽虹, 尤嘉琮,乔玲等。应用基因表达谱芯片从不同转移能力的乳腺癌细胞中筛选转移相关基因。生物化学与生物物理进展,2005,32：421-428。
[186]Schuierer, M.M., Bataille, F., Weiss, T.S., Hellerbrand, C. and Bosserhoff, A.K. (2006). Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 16, 451-456.
[187]Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J. and Saltiel, A.R. (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92, 7686-7689.
[188]Favata, M.F. et al. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273,18623-18632.
[189]Sebolt-Leopold, J.S. and Herrera, R. (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4,937-947.
[190]Boucher, M.J., Morisset,J., Vachon, P.H., Reed, J.C., Laine, J. and Rivard, N. (2000). MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79,355-369.
[191]Murphy, L.O. et al. (2001). Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions. Br J Cancer 84,926-935.
[192]Xing, C. and Imagawa, W. (1999). Altered MAP kinase (ERK1,2) regulation in primary cultures of mammary tumor cells:elevated basal activity and sustained response to EGF. Carcinogenesis 20,1201-1208.
[193]Duncia, J.V. et al. (1998). MEK inhibitors:the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8,2839-2844.
[194]Sebolt-Leopold, J.S. et al. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5,810-816.
[195]Lorusso, P.M. et al. (2005). Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23,5281-5293.
[196]Yeh, T.C. et al. (2007). Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13, 1576-1583.
[197]Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. and Pandolfi, P.P. (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121,179-193.
[198]Montaner, S., Sodhi, A., Pece, S., Mesri, E.A. and Gutkind, J.S. (2001) The Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Promotes Endothelial Cell Survival through the Activation of Akt/Protein Kinase. Cancer Res 61,2641-2648.
[199]Wang, X. et al. (2007). Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol Cell Biol 27,7405-7413.
[200]Wohlbold, L., van der Kuip, H., Miething, C., Vornlocher, H.P., Knabbe, C., Duyster, J. and Aulitzky, W.E. (2003). Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 102,2236-2239.
[201]Fan, Q.W., Cheng, C.K., Nicolaides, T.P., Hackett, C.S., Knight, Z.A., Shokat. K.M. and Weiss, W.A. (2007). A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67,7960-7965.
[202]Fan, Q.W., Knight, Z.A., Goldenberg, D.D., Yu, W., Mostov, K.E., Stokoe, D., Shokat, K.M. and Weiss, W.A. (2006). A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9,341-349.
[203]Knight, Z.A. et al. (2006). A Pharmacological Map of the PI3-K Family Defines a Role for p110[alpha] in Insulin Signaling. Cell 125,733-747.
[204]Kojima, K. et al. (2008). The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22,1728-1736.
[205]Park, S. et al. (2008). PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22,1698-1706.
[206]Chaisuparat, R., Hu, J., Jham, B.C., Knight, Z.A., Shokat, K.M. and Montaner, S. (2008). Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res 68,8361-8368.
[207]Chen, J.S. et al. (2008). Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7,841-850.
[208]Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E. and Thun, M.J. (2003). Cancer Statistics,2003. CA Cancer J Clin 53,5-26.
[209]Haeder, M., Rotsch, M., Bepler, G., Hennig, C., Havemann, K., Heimann, B. and Moelling, K. (1988). Epidermal growth factor receptor expression in human lung cancer cell lines. Cancer Res 48,1132-1136.
[210]Nicholson, R.I., Gee, J.M. and Harper, M.E. (2001). EGFR and cancer prognosis. Eur J Cancer 37 Suppl 4,9-15.
[211]Ohsaki, Y. et al. (2000). Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7, 603-607.
[212]Lynch, T.J. et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350, 2129-2139.
[213]Paez, J.G. et al. (2004). EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science 304,1497-1500.
[214]Pao, W. et al. (2004). EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101,13306-13311.
[215]Massion, P.P. et al. (2004). Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med 170,1088-1094.
[216]Tsurutani, J. et al. (2007). Prognostic significance of clinical factors and Akt activation in patients with bronchioloalveolar carcinoma. Lung Cancer 55,115-121.
[217]Mitsudomi, T. et al. (1991). ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 51, 4999-5002.
[218]Rodenhuis, S., van de Wetering, M.L., Mooi, W.J., Evers, S.G., van Zandwijk, N. and Bos, J.L. (1987). Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 317,929-935.
[219]Singh, R.P., Agarwal, C. and Agarwal, R. (2003). Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells:modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis 24, 555-563.
[220]Galea, C.A., Wang, Y., Sivakolundu, S.G. and Kriwacki, R.W. (2008). Regulation of cell division by intrinsically unstructured proteins:intrinsic flexibility, modularity, and signaling conduits. Biochemistry 47,7598-7609.
[221]Burkhard, S.J. and Traugh, J.A. (1983). Changes in Ribosome Function by Camp-Dependent and Camp-Independent Phosphorylation of Ribosomal Protein-S6. J Biol Chem 258,4003-4008.
[222]Thomas, G., Siegmann, M. and Gordon, J. (1979). Multiple phosphorylation of ribosomal protein S6 during transition of quiescent 3T3 cells into early G1, and cellular compartmentalization of the phosphate donor. Proc Natl Acad Sci U S A 76,3952-3956.
[223]Roux, P.P., Shahbazian, D., Vu, H., Holz, M.K., Cohen, M.S., Taunton, J.. Sonenberg, N. and Blenis, J. (2007). RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282, 14056-14064.
[224]Shahbazian, D. et al. (2006). The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. Embo J 25,2781-2791.
[225]Chou, T.C. and Talalay, P. (1984). Quantitative analysis of dose-effect relationships:the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22,27-55.
[226]Janmaat, M.L., Rodriguez, J.A., Gallegos-Ruiz, M., Kruyt, F.A. and Giaccone, G. (2006). Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer 118,209-214.
[227]Sun, S.Y., Rosenberg, L.M., Wang, X.R., Zhou, Z.M., Yue, P., Fu, H. and Khuri, F.R. (2005). Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Research 65,7052-7058.
[228]Holz, M.K., Ballif, B.A., Gygi, S.P. and Blenis, J. (2005). mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123,569-580.
[229]Buck, E. et al. (2006). Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Thera 5,2676-2684.
[230]Whyte, D.B. and Holbeck, S.L. (2006). Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem Biophys Res Commun 340, 469-475.
[231]Sharma, S.V. et al. (2006). A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10,425-435.
[232]Sharma, S.V., Fischbach, M.A., Haber, D.A. and Settleman, J. (2006). "Oncogenic shock": explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 12, 4392-4395.
[233]Park, S. et al. (2007). PI-103. a dual inhibitor of class I phosphatidylinositide 3-kinase and mTOR. has anti-leukemic activity in acute myeloid leukemia. Blood 110,1-10.
[234]Fan, Q.-W., Cheng, C.K., Nicolaides, T.P., Hackett, C.S., Knight, Z.A., Shokat, K.M. and Weiss, W.A. (2007). A Dual Phosphoinositide-3-Kinase{alpha}/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma. Cancer Res 67,7960-7965.
[235]Legrier, M.E., Yang, C.P., Yan, H.G., Lopez-Barcons, L., Keller, S.M., Perez-Soler, R., Horwitz, S.B. and McDaid, H.M. (2007). Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 67,11300-11308.
[236]Chun, P.Y., Feng, F.Y., Scheurer, A.M., Davis, M.A, Lawrence, T.S. and Nyati, M.K. (2006). Synergistic effects of gemcitabine and gefitinib in the treatment of head and neck carcinoma. Cancer Res 66,981-988.
[237]Nakamura, H., Takamori, S., Fujii, T., Ono, M., Yamana, H., Kuwano, M. and Shirouzu, K. (2005). Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. Cancer Lett 230, 33-46.
[238]Molhoek, K.R., Brautigan, D.L. and Slingluff, C.L., Jr. (2005). Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J Transl Med 3,39-50.
[239]Maione, P., Gridelli, C., Troiani, T. and Ciardiello, F. (2006). Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist 11, 274-284.
[240]于小云。紫杉醇加顺铂治疗晚期非小细胞肺癌的临床观察。现代中西医结合杂志,2008,17：5130-5130.
[241]张燕 和 董建红。紫杉醇抗肿瘤作用机制研究现状。现代中西医结合杂志,2005,14：3312-3313。
[242]Sumitomo, M., Asano, T., Asakuma, J., Asano, T., Horiguchi, A. and Hayakawa, M. (2004). ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin Cancer Res 10,794-801.
[243]Maione, P., Gridelli, C., Troiani, T. and Ciardiello, F. (2006). Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC. The Oncologist 11,274-284.
[244]Hu, Y., Bally, M., Dragowska, W.H. and Mayer, L. (2003). Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. Mol Cancer Ther 2,641-649.
[245]McDaid, H.M., Lopez-Barcons, L., Grossman, A., Lia, M., Keller, S., Perez-Soler, R. and Horwitz, S.B. (2005). Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. Cancer Res 65,2854-2860.
[246]Nguyen, D.M., Chen, G.A., Reddy, R., Tsai, W., Schrump, W.D., Cole, G., Jr. and Schrump, D.S. (2004). Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway. J Thorac Cardiovasc Surg 127,365-375.
[247]Philipp-Staheli, J., Kim, K.H., Liggitt, D., Gurley, K.E., Longton, G. and Kemp, C.J. (2004). Distinct roles for p53, p27Kipl, and p21Cipl during tumor development. Oncogene 23,905-913.
[248]Danial, N.N. et al. (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424,952-956.
[249]Han, E.K., Gehrke, L., Tahir, S.K., Credo, R.B., Cherian, S.P., Sham, H., Rosenberg, S.H. and Ng, S. (2000). Modulation of drug resistance by alpha-tubulin in paclitaxel-resistant human lung cancer cell lines. Eur J Cancer 36,1565-1571.
[250]Bacus, S.S. et al. (2001). Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20,147-155.
[251]Kawaguchi, W. et al. (2007). Simultaneous inhibition of the mitogen-activated protein kinase kinase and phosphatidylinositol 3'-kinase pathways enhances sensitivity to paclitaxel in ovarian carcinoma. Cancer Sci 98,2002-2008.
[252]Shi, Y. et al. (2005). Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Neoplasia 7,992-1000.
[253]肖颖 和 赵玉斌。红豆杉中紫杉醇抗癌研究进展。现代中西医结合杂志,2008,17：5557-5558。
[254]施亚军。晚期结肠癌分子靶向治疗的研究进展。现代中西医结合杂志,2007,16：1145-1147.
[255]Hurwitz, H. et al. (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350,2335-2342.
[256]Hollywood, E. (2002). Clinical issues in the administration of an anti-epidermal growth factor receptor monoclonal antibody, IMC-C225. Semin Oncol Nurs 18,30-35.
[257]Loeffler-Ragg, J., Skvortsov, S., Sarg, B., Skvortsova, I., Witsch-Baumgartner, M., Mueller, D., Lindner, H. and Zwierzina, H. (2005). Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines. Eur J Cancer 41,2338-2346.
[258]叶胜龙。关注原发性肝癌的靶向治疗研究。中华肝脏病杂志,20005,13：322-323。
[259]Sutter, A.P., Hopfner, M., Huether, A., Maaser, K. and Scherubl, H. (2006). Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer. Int J Cancer 118,1814-1822.
[260]Zhang, X., Gaspard, J.P. and Chung, D.C. (2001). Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res 61, 6050-6054.
[261]Yu, C., Friday, B.B., Lai, J.P., McCollum, A., Atadja, P., Roberts, L.R. and Adjei, A.A. (2007). Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin Cancer Res 13,1140-1148.
[262]Dai, Y., Rahmani, M., Pei, X.Y., Khanna, P., Han, S.I., Mitchell, C., Dent, P. and Grant, S. (2005). Farnesyltransferase inhibitors interact synergistically with the Chkl inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 105,1706-1716.
[263]Mukohara. T., Civiello, G., Johnson, B.E. and Janne, P.A. (2005). Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma. Oncology 68,500-510.
[264]Greenhough, A., Patsos, H.A., Williams, A.C. and Paraskeva. C. (2007). The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer 121, 2172-2180.
[265]Guillard, S. et al. (2009). Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 8,443-453.
[266]MacKeigan, J.P., Taxman, D.J., Hunter, D., Earp, H.S.,3rd, Graves, L.M. and Ting, J.P. (2002). Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase kinase inhibition. Clin Cancer Res 8,2091-2099.
[267]Zhu, K. et al. (2005). Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Blood 105,4759-4766.
[268]Mabuchi, S. et al. (2002). Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem 277,33490-33500.
[269]周鸿,山杉公男。Dha对大白鼠血胆固醇浓度及磷脂分子组成的影响.江西科学,2003,21：95-100。
[270]Ding, W.Q. and Lind, S.E. (2007). Phospholipid hydroperoxide glutathione peroxidase plays a role in protecting cancer cells from docosahexaenoic acid-induced cytotoxicity. Mol Cancer Ther 6,1467-1474.
[271]Hardman, W.E. (2007). Dietary canola oil suppressed growth of implanted MDA-MB 231 human breast tumors in nude mice. Nutr Cancer 57,177-183.
[272]Khan, N.A., Nishimura, K., Aires, V., Yamashita, T., Oaxaca-Castillo, D., Kashiwagi, K. and Igarashi, K. (2006). Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation. J Lipid Res 47,2306-2313.
[273]Rose, D.P. and Connolly, J.M. (1999). Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 83,217-244.
[274]Liu, G., Bibus, D.M., Bode, A.M., Ma, W.Y., Holman, R.T. and Dong, Z. (2001). Omega 3
but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proc Natl Acad Sci U S A 98,7510-7515.
[275]Brown, M., Bellon, M. and Nicot, C. (2007). Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-1-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1. Blood 109,1653-1659.
[276]王静,糜漫天, 韦娜 和 王斌。不同膳食脂肪酸构成对乳腺癌大鼠brcal表达的影响.实用医药杂志,2007,24：84-86。
[277]Akbar, M., Calderon, F., Wen, Z. and Kim, H.Y. (2005). Docosahexaenoic acid:a positive modulator of Akt signaling in neuronal survival. Proc Natl Acad Sci U S A 102, 10858-10863.
[278]Maheo, K., Vibet, S., Steghens, J.P., Dartigeas, C., Lehman, M., Bougnoux, P. and Gore, J. (2005). Differential sensitization of cancer cells to doxorubicin by DHA:a role for lipoperoxidation. Free Radic Biol Med 39,742-751.
[279]Kishida, E., Tajiri, M. and Masuzawa, Y. (2006). Docosahexaenoic acid enrichement can reduce L929 cell necrosis induced by tumor necrosis factor. Biochim Biophys Acta 1761,454-462.