拉帕替尼诱导HER2阳性乳腺癌细胞凋亡机制及其与ABT-737的协同抗肿瘤作用
摘要
目的：(1)探讨BH3-Only蛋白在拉帕替尼诱导Her2阳性乳腺癌细胞凋亡中的作用及其与FOXO3a蛋白的关系；(2)研究ABT-737和拉帕替尼联合应用与Her2阳性的SK-BR3细胞的联合作用及其机制。
方法：(1)流式细胞仪Annexin V染色的方法检测细胞凋亡,Real TimePCR和Western blot检测Her2信号通路相关蛋白、BH3-Only家族蛋白和FOXO3a蛋白的表达在拉帕替尼处理后的差异,SiRNA技术抑制Bim和FOXO3a蛋白的表达,确定它们在拉帕替尼诱导的细胞凋亡中的作用以及FOXO3a蛋白对Bim蛋白表达的调控。(2)CCK-8法研究拉帕替尼和ABT-737单用和联合应用的细胞效应,利用中位效应原理并使用Calcusyn软件分析两药的联合作用。Western blot检测BCL-2家族蛋白在拉帕替尼单用和联合应用ABT-737后的变化,免疫共沉淀法检测ABT-737对BCL-2蛋白拮抗Bim蛋白促凋亡活性的抑制作用。
结果：(1)拉帕替尼作用于HER阳性乳腺癌细胞株BT-474和SK-BR3,诱导细胞发生凋亡并伴有Caspase 3和BAX蛋白的激活,促凋亡的BH3-Only家族蛋白之一Bim蛋白和FOXO3a的表达增多,SiRNA抑制Bim和FOXO3a的表达,能够抑制拉帕替尼诱导的细胞凋亡,抑制FOXO3a表达的同时,Bim蛋白表达降低。(2)ABT-737和拉帕替尼联合应用于SK-BR3细胞能够产生协同作用；拉帕替尼诱导SK-BR3细胞Bim蛋白表达增高,抗凋亡的MCL-1蛋白表达降低；拉帕替尼诱导Bim蛋白表达增多同时与BCL-2蛋白结合也增多,ABT-737和拉帕替尼联合应用未改变拉帕替尼对BCL-2家族蛋白表达变化的影响,但是能够抑制BCL-2蛋白和Bim蛋白的结合。
结论：(1)拉帕替尼能够诱导HER2阳性乳腺癌细胞BT474和SK-BR3细胞发生凋亡,拉帕替尼诱导细胞凋亡可能通过转录激活激活Bim蛋白的表达,激活线粒体细胞凋亡途径促进细胞发生凋亡,Bim蛋白的表达受FOXO3a蛋白的调控,因此,拉帕替尼可能通过抑制PI3K/AKT信号通路,促进FOXO3a蛋白的表达增多,转录激活Bim蛋白的表达,激活线粒体细胞凋亡途径是细胞发生凋亡。(2)ABT-737和拉帕替尼联合应用于Her2阳性的乳腺癌细胞SK-BR3能够产生协同作用,其协同作用的机制可能为一方面拉帕替尼抑制了抗凋亡蛋白MCL-1蛋白的表达,促进了ABT-737的抗肿瘤效应,另一方面ABT-737抑制了拉帕替尼诱导Bim蛋白表达增多同时发生的与BCL-2蛋白的结合增多,促进了Bim蛋白的促凋亡活性。
Objective:(1) To explore the role of BH3-Only family proteins in the apoptosis induced by Lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 cells and whether regulated by FOXO3a protein. (2) To study the synergy effect between BH3 mimitic compound, ABT-737 and Lapatinib in Her2 positive breast cancer cell SK-BR3 and explore the mechanism of the synergy effect.
Methods:(1) The extent of apoptosis was evaluated by flow cytometric analysis utilizing annexin V-fluorescein isothiocyanate staining method. The Her2 pathway protein, BH3-Only family protein and protein FOXO3a were measured by Real-time PCR and Western blot methods. RNA interference method inhibiting the express of Bim and FOXO3a protein to ascertain the role of them in the apoptosis induced by lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 and whether Bim expression regulated by FOXO3a protein. (2). Utilize CCK8 method to study the toxic effect of BH3 mimitic compound, ABT-737 and Lapatinib in the Her2 positive breast cancer cell SK-BR3. According median-effect principal (Chou-Talalay combination index method), utilize the Calcusyn software analysis the combination index (CI) to ascertain the synergistic effective between them in SK-BR3 cell. The difference of BCL-2 family proteins induced by Lapatinib alone or combined with ABT-737 in SK-BR3 cell was detected by Western blot method. The association of BCL-2 and Bim protein was detected by Coimmunoprecipitation method.
Result:(1). The apoptosis induced by Lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 cells accompanied by a pronounced increase of Caspase 3 cleavage and the conformational change of BAX. The expression of one of the BH3-only family protein Bim and FOXO3a increase after treatment of Lapatinib. RNA interference of Bim and FOXO3a inhibit the apoptosis induced by Lapatinib in SK-BR3 cell, and the increase of Bim protein induced by Lapatinib was inhibited by RNA interference of FOXO3a. (2) The BH3-mimitci compound ABT-737 synergizes the antitumor activity of Lapatinib in SK-BR3 cell. With the increase of Bim protein induced by Lapatinib the expression of MCL-1 protein was decreased. Lapatinib-induced Bim is primarily sequestered by Bcl-2 rather than Mcl-1 and Bcl-xL; these associations are disrupted by ABT-737.
Conclusion:(1) Lapatinib induced apoptosis require Bim through mitochondrial pathway and regulated by FOXO3a in Her2 positive breast cancer cells. The AKT-FOXO3a-Bim axis may be the important role in lapatinib induced apoptosis. (2) The BH3 mimetic compound ABT-737 synergize the antitumor activity of Lapatinib for Her2 positive breast cancer cell SK-BR3. The mechanism may be the Lapatinib induced decrease of MCL-1 protein enhancing the activity of ABT-737, on the other hand ABT-737 disrupted the associations in Lapatinib-induced Bim sequestered by Bcl-2.
方法：(1)流式细胞仪Annexin V染色的方法检测细胞凋亡,Real TimePCR和Western blot检测Her2信号通路相关蛋白、BH3-Only家族蛋白和FOXO3a蛋白的表达在拉帕替尼处理后的差异,SiRNA技术抑制Bim和FOXO3a蛋白的表达,确定它们在拉帕替尼诱导的细胞凋亡中的作用以及FOXO3a蛋白对Bim蛋白表达的调控。(2)CCK-8法研究拉帕替尼和ABT-737单用和联合应用的细胞效应,利用中位效应原理并使用Calcusyn软件分析两药的联合作用。Western blot检测BCL-2家族蛋白在拉帕替尼单用和联合应用ABT-737后的变化,免疫共沉淀法检测ABT-737对BCL-2蛋白拮抗Bim蛋白促凋亡活性的抑制作用。
结果：(1)拉帕替尼作用于HER阳性乳腺癌细胞株BT-474和SK-BR3,诱导细胞发生凋亡并伴有Caspase 3和BAX蛋白的激活,促凋亡的BH3-Only家族蛋白之一Bim蛋白和FOXO3a的表达增多,SiRNA抑制Bim和FOXO3a的表达,能够抑制拉帕替尼诱导的细胞凋亡,抑制FOXO3a表达的同时,Bim蛋白表达降低。(2)ABT-737和拉帕替尼联合应用于SK-BR3细胞能够产生协同作用；拉帕替尼诱导SK-BR3细胞Bim蛋白表达增高,抗凋亡的MCL-1蛋白表达降低；拉帕替尼诱导Bim蛋白表达增多同时与BCL-2蛋白结合也增多,ABT-737和拉帕替尼联合应用未改变拉帕替尼对BCL-2家族蛋白表达变化的影响,但是能够抑制BCL-2蛋白和Bim蛋白的结合。
结论：(1)拉帕替尼能够诱导HER2阳性乳腺癌细胞BT474和SK-BR3细胞发生凋亡,拉帕替尼诱导细胞凋亡可能通过转录激活激活Bim蛋白的表达,激活线粒体细胞凋亡途径促进细胞发生凋亡,Bim蛋白的表达受FOXO3a蛋白的调控,因此,拉帕替尼可能通过抑制PI3K/AKT信号通路,促进FOXO3a蛋白的表达增多,转录激活Bim蛋白的表达,激活线粒体细胞凋亡途径是细胞发生凋亡。(2)ABT-737和拉帕替尼联合应用于Her2阳性的乳腺癌细胞SK-BR3能够产生协同作用,其协同作用的机制可能为一方面拉帕替尼抑制了抗凋亡蛋白MCL-1蛋白的表达,促进了ABT-737的抗肿瘤效应,另一方面ABT-737抑制了拉帕替尼诱导Bim蛋白表达增多同时发生的与BCL-2蛋白的结合增多,促进了Bim蛋白的促凋亡活性。
Objective:(1) To explore the role of BH3-Only family proteins in the apoptosis induced by Lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 cells and whether regulated by FOXO3a protein. (2) To study the synergy effect between BH3 mimitic compound, ABT-737 and Lapatinib in Her2 positive breast cancer cell SK-BR3 and explore the mechanism of the synergy effect.
Methods:(1) The extent of apoptosis was evaluated by flow cytometric analysis utilizing annexin V-fluorescein isothiocyanate staining method. The Her2 pathway protein, BH3-Only family protein and protein FOXO3a were measured by Real-time PCR and Western blot methods. RNA interference method inhibiting the express of Bim and FOXO3a protein to ascertain the role of them in the apoptosis induced by lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 and whether Bim expression regulated by FOXO3a protein. (2). Utilize CCK8 method to study the toxic effect of BH3 mimitic compound, ABT-737 and Lapatinib in the Her2 positive breast cancer cell SK-BR3. According median-effect principal (Chou-Talalay combination index method), utilize the Calcusyn software analysis the combination index (CI) to ascertain the synergistic effective between them in SK-BR3 cell. The difference of BCL-2 family proteins induced by Lapatinib alone or combined with ABT-737 in SK-BR3 cell was detected by Western blot method. The association of BCL-2 and Bim protein was detected by Coimmunoprecipitation method.
Result:(1). The apoptosis induced by Lapatinib in Her2 positive breast cancer cells BT-474 and SK-BR3 cells accompanied by a pronounced increase of Caspase 3 cleavage and the conformational change of BAX. The expression of one of the BH3-only family protein Bim and FOXO3a increase after treatment of Lapatinib. RNA interference of Bim and FOXO3a inhibit the apoptosis induced by Lapatinib in SK-BR3 cell, and the increase of Bim protein induced by Lapatinib was inhibited by RNA interference of FOXO3a. (2) The BH3-mimitci compound ABT-737 synergizes the antitumor activity of Lapatinib in SK-BR3 cell. With the increase of Bim protein induced by Lapatinib the expression of MCL-1 protein was decreased. Lapatinib-induced Bim is primarily sequestered by Bcl-2 rather than Mcl-1 and Bcl-xL; these associations are disrupted by ABT-737.
Conclusion:(1) Lapatinib induced apoptosis require Bim through mitochondrial pathway and regulated by FOXO3a in Her2 positive breast cancer cells. The AKT-FOXO3a-Bim axis may be the important role in lapatinib induced apoptosis. (2) The BH3 mimetic compound ABT-737 synergize the antitumor activity of Lapatinib for Her2 positive breast cancer cell SK-BR3. The mechanism may be the Lapatinib induced decrease of MCL-1 protein enhancing the activity of ABT-737, on the other hand ABT-737 disrupted the associations in Lapatinib-induced Bim sequestered by Bcl-2.
引文
1. Jemal, A., et al., Cancer statistics,2008. Ca-a Cancer Journal for Clinicians, 2008.58(2):p.71-96.
2. Chanan-Khan, A.A., et al., Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma,2009.50(4):p.559-65.
3. Schimmer, A.D., et al., Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell,2004.5(1):p.25-35.
4. Campiglio, M., et al., Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level. J Cell Physiol,2004.198(2):p.259-68.
5. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
6. Ciardiello, F. and G. Tortora, A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clinical Cancer Research, 2001.7(10):p.2958-2970.
7. Webb, A., et al., BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet,1997.349(9059):p.1137-1141.
8. Antonarakis, E.S., M.A. Carducci, and M.A. Eisenberger, Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett, 2010.291(1):p.1-13.
9. Rowinsky, E.K., The erbB family:targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med,2004.55:p.433-57.
10. Yarden, Y. and M.X. Sliwkowski, Untangling the ErbB signalling network. Nat Rev Mol Cell Biol,2001.2(2):p.127-37.
11. Moy, B. and P.E. Goss, Lapatinib:current status and future directions in breast cancer. Oncologist,2006.11(10):p.1047-57.
12. Herbst, R.S. and D.M. Shin, Monoclonal antibodies to target epidermal growth factor receptor-positive tumors:a new paradigm for cancer therapy. Cancer,2002.94(5):p.1593-611.
13. Nahta, R., G.N. Hortobagyi, and F.J. Esteva, Growth factor receptors in breast cancer:potential for therapeutic intervention. Oncologist,2003.8(1):p.5-17.
14. Wood, E.R., et al., A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib):relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res,2004. 64(18):p.6652-9.
15. McArthur, H.,An overview of HER-targeted therapy with lapatinib in breast cancer. Adv Ther,2009.26(3):p.263-71.
16. Nahta, R., et al., Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells:effects on insulin-like growth factor Ⅰ signaling. Mol Cancer Ther, 2007.6(2):p.667-74.
17. Lin, N.U., et al., Multicenter phase Ⅱ study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res,2009.15(4):p. 1452-9.
18. Lin, N.U., et al., Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol,2008.26(12):p.1993-9.
19. Haunstetter, A. and S. Izumo, Apoptosis:basic mechanisms and implications for cardiovascular disease. Circ Res,1998.82(11):p.1111-29.
20. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
21. El-Zawahry, A., J. McKillop, and C. Voelkel-Johnson, Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer,2005.5:p.2.
22. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
23. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
24. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
25. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
26. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
27. Slamon, D.J., et al., Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science,1989.244(4905):p.707-12.
28. Xia, W., et al., Anti-tumor activity of GW572016:a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erkl/2 and AKT pathways. Oncogene,2002.21(41):p.6255-63.
29. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
30. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
31. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
32. Letai, A.G., Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer,2008.8(2):p.121-32.
33. Willis, S.N., et al., Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science,2007.315(5813):p.856-9.
34. Bouillet, P., et al., Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome,2001.12(2): p.163-8.
35. Strasser, A., et al., What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol, 2008.86(1):p.57-66.
36. Marani, M., et al., Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol,2002. 22(11):p.3577-89.
37. Jacobs, F.M., et al., FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem,2003.278(38):p. 35959-67.
38. Tsai, K.L., et al., Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res, 2007.35(20):p.6984-94.
39. Yamamura, Y., et al., RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. J Biol Chem,2006.281(8):p.5267-76.
40. Sunters, A., et al., Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res,2006.66(1):p.212-20.
41. Van Der Heide, L.P., M.F. Hoekman, and M.P. Smidt, The ins and outs of FoxO shuttling:mechanisms of FoxO translocation and transcriptional regulation. Biochem J,2004.380(Pt 2):p.297-309.
42. Li, S., et al., Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther,2007.6(3):p.1031-8.
43. Xia, W., et al., A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A,2006.103(20):p.7795-800.
44. Hegde, P.S., et al., Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther,2007.6(5):p.1629-40.
1. Jemal, A., et al., Cancer statistics,2008. Ca-a Cancer Journal for Clinicians, 2008.58(2):p.71-96.
2. Lowe, S.W. and A.W. Lin, Apoptosis in cancer. Carcinogenesis,2000.21(3):p. 485-95.
3. Nicholson, D.W. and N.A. Thornberry, Apoptosis. Life and death decisions. Science,2003.299(5604):p.214-5.
4. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
5. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
6. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
7. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
8. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
9. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
10. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
11. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
12. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
13. Letai, A.G., Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer,2008.8(2):p.121-32.
14. Willis, S.N., et al., Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science,2007.315(5813):p.856-9.
15. Bouillet, P., et al., Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome,2001.12(2): p.163-8.
16. Strasser, A., et al., What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol, 2008.86(1):p.57-66.
17. Marani, M., et al., Identification of novel isoforms of the BH3 domain protein Bim which directly activate Box to trigger apoptosis. Mol Cell Biol,2002. 22(11):p.3577-89.
18. Lackey, K.E., Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. Curr Top Med Chem,2006.6(5):p.435-60.
19. Xia, W., et al., Anti-tumor activity of GW572016:a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erkl/2 and AKT pathways. Oncogene,2002.21(41):p.6255-63.
20. Xia, W., et al., Regulation of survivin by ErbB2 signaling:therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res,2006. 66(3):p.1640-7.
21. Kopper, L., Lapatinib:a sword with two edges. Pathol Oncol Res,2008.14(1): p.1-8.
22. Oltersdorf, T., et al., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature,2005.435(7042):p.677-81.
23. Chauhan, D., et al., A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene,2007.26(16):p.2374-80.
24. Hann, C.L., et al., Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res,2008.68(7):p.2321-8.
25. Cory, S. and J.M. Adams, Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell,2005.8(1):p.5-6.
26. Chen, S., et al., Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Box translocation. Cancer Res, 2007.67(2):p.782-91.
27. Konopleva, M, et al., Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell,2006. 10(5):p.375-88.
28. Lin, X., et al.,'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene,2007.26(27):p.3972-9.
29. Tahir, S.K., et al., Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res,2007.67(3):p. 1176-83.
30. van Delft, M.F., et al., The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell,2006.10(5):p.389-99.
31. Kang, M.H., et al., Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines:Mcl-1 inactivation. J Natl Cancer Inst,2008.100(8):p.580-95.
32. Del Gaizo Moore, V., et al., Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest,2007.117(1):p.112-21.
33. Berenbaum, M.C., What is synergy? Pharmacol Rev,1989.41(2):p.93-141.
34. Koch, G., et al., Modeling of tumor growth and anticancer effects of combination therapy. J Pharmacokinet Pharmacodyn,2009.36(2):p.179-97.
35. Peterson, J.J., A review of synergy concepts of nonlinear blending and dose-reduction profiles. Front Biosci (Schol Ed),2010.2:p.483-503.
36. Chou, T.C., et al., Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth:a rational approach to clinical protocol design. J Natl Cancer Inst,1994.86(20): p.1517-24.
37. Chou, T.C., Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res,2010.70(2):p.440-6.
38. Cox, E., Synergy in practice:caring for victims of intimate partner violence. Crit Care Nurs Q,2003.26(4):p.323-30.
39. Ferreira, C.G., et al., Apoptosis:target of cancer therapy. Clin Cancer Res, 2002.8(7):p.2024-34.
40. Reed, J.C., Bcl-2 family proteins:regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol,1997.34(4 Suppl 5):p.9-19.
41. Hockenbery, D., et al., Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature,1990.348(6299):p.334-6.
42. Cory, S. and J.M. Adams, The Bcl2 family:regulators of the cellular life-or-death switch. Nat Rev Cancer,2002.2(9):p.647-56.
43. Letai, A., Pharmacological manipulation of Bcl-2 family members to control cell death. J Clin Invest,2005.115(10):p.2648-55.
44. Letai, A., et al., Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell,2004.6(3):p.241-9.
45. Reed, J.C. and M. Pellecchia, Apoptosis-based therapies for hematologic malignancies. Blood,2005.106(2):p.408-18.
46. Adams, J.M. and S. Cory, The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene,2007.26(9):p.1324-37.
47. Zhao, Y, et al., Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci U S A,2005.102(44):p.16090-5.
48. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
49. Tse, C., et al., ABT-263:a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res,2008.68(9):p.3421-8.
50. Cheng, E.H., et al., BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell,2001. 8(3):p.705-11.
51. Kim, H., et al., Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol,2006.8(12):p.1348-58.
52. Letai, A., et al., Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell,2002.2(3):p.183-92.
53. Certo, M., et al., Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell,2006.9(5):p. 351-65.
1. Lowe, S.W. and A.W. Lin, Apoptosis in cancer. Carcinogenesis,2000.21(3):p. 485-95.
2. Hengartner, M.O., The biochemistry of apoptosis. Nature,2000.407(6805):p. 770-6.
3. Hockenbery, D., et al., Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature,1990.348(6299):p.334-6.
4. Zapata, J.M., et al., A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. J Biol Chem,2001.276(26):p. 24242-52.
5. Scaffidi, C., et al., Two CD95 (APO-1/Fas) signaling pathways. EMBO J, 1998.17(6):p.1675-87.
6. Landowski, T.H., et al., CD95 antigen mutations in hematopoietic malignancies. Leuk Lymphoma,2001.42(5):p.835-46.
7. Lamy, T., et al., Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD3(+) large granular lymphocyte leukemia. Blood,1998.92(12):p.4771-7.
8. Tsujimoto, Y., et al., Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome trans location. Science,1984.226(4678):p. 1097-9.
9. Reed, J.C., Bcl-2 family proteins:regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol,1997.34(4 Suppl 5):p.9-19.
10. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
11. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
12. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
13. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
14. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
15. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
16. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
17. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
18. Mancini, M., et al., The caspase-3 precursor has a cytosolic and mitochondrial distribution; implications for apoptotic signaling. J Cell Biol, 1998.140(6):p.1485-95.
19. Thornberry, N.A. and Y. Lazebnik, Caspases:enemies within. Science,1998. 281(5381):p.1312-6.
20. Benchimol, S., p53-dependent pathways of apoptosis. Cell Death Differ,2001. 8(11):p.1049-51.
21. Yu, J., et al., Puma mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A,2003.100(4):p.1931-6.
22. Maldonado, V., J. Melendez-Zajgla, and A. Ortega, Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. Mutat Res,1997. 381(1):p.67-75.
23. Kuhnel, F., et al., NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. J Biol Chem,2000.275(9):p. 6421-7.
24. Myung, J., K.B. Kim, and C.M. Crews, The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev,2001.21(4):p.245-73.
25. Wu, W.K., et al., Proteasome inhibition:A new therapeutic strategy to cancer treatment. Cancer Lett,2010.
26. Adams, J., et al., Proteasome inhibitors:a novel class of potent and effective antitumor agents. Cancer Res,1999.59(11):p.2615-22.
27. Hidalgo, M. and E.K. Rowinsky, The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene,2000.19(56):p.6680-6.
28. Cantley, L.C., The phosphoinositide 3-kinase pathway. Science,2002. 296(5573):p.1655-7.
29. Wen, Y., et al., HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res,2000. 60(24):p.6841-5.
30. Cantley, L.C. and B.G. Neel, New insights into tumor suppression:PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A,1999.96(8):p.4240-5.
31. Dancey, J.E., Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am,2002.16(5):p.1101-14.
32. Wang, X., et al., Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem,2000.275(19):p. 14624-31.
33. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
34. Choi, I.J., et al., Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. Infect Immun,2003.71(2):p.830-7.
35. Liesveld, J.L., et al., Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia,2003.17(9):p.1806-12.
36. Adachi, S., et al., Apoptosis induced by molecular targeting therapy in hematological malignancies. Acta Haematol,2004.111(1-2):p.107-23.
37. Ivy, P.S. and M. Schoenfeldt, Clinical trials referral resource. Current clinical trials of 17-AG and 17-DMAG. Oncology (Williston Park),2004.18(5):p.610, 615,619-20.
38. Mei, S., A.D. Ho, and U. Mahlknecht, Role of histone deacetylase inhibitors in the treatment of cancer (Review). Int J Oncol,2004.25(6):p.1509-19.
39. Campiglio, M., et al., Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level. J Cell Physiol,2004.198(2):p.259-68.
40. Rinehart, J., et al., Multicenter phase Ⅱ study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol,2004.22(22):p.4456-62.
41. Troppmair, J. and U.R. Rapp, Raf and the road to cell survival:a tale of bad spells, ring bearers and detours. Biochem Pharmacol,2003.66(8):p.1341-5.
42. de Vries, E.G., et al., Correspondence re:C. G. Ferreira et al., Apoptosis: target of cancer therapy. Clin. Cancer Res.,8:2024-2034,2002. Clin Cancer Res,2003.9(2):p.912; author reply 913.
43. Tolcher, A.W., Regulators of apoptosis as anticancer targets. Hematol Oncol Clin North Am,2002.16(5):p.1255-67.
44. Havell, E.A., W. Fiers, and R.J. North, The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med,1988.167(3):p.1067-85.
45. Ogasawara, J., et al., Lethal effect of the anti-Fas antibody in mice. Nature, 1993.364(6440):p.806-9.
46. Ferreira, C.G., et al., Apoptosis:target of cancer therapy. Clin Cancer Res, 2002.8(7):p.2024-34.
47. El-Zawahry, A., J. McKillop, and C. Voelkel-Johnson, Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer,2005.5:p.2.
48. Chuntharapai, A., et al., Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol,2001.166(8):p. 4891-8.
49. Plummer, R., et al., Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res,2007.13(20):p.6187-94.
50. Altucci, L., et al., Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med, 2001.7(6):p.680-6.
51. Chou, W.C. and C.V. Dang, Acute promyelocytic leukemia:recent advances in therapy and molecular basis of response to arsenic therapies. Curr Opin Hematol,2005.12(1):p.1-6.
52. Chen, Z., Z.Y. Wang, and S J. Chen, Acute promyelocytic leukemia:cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther,1997. 76(1-3):p.141-9.
53. Hussein, M.A., et al., Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol,2004.125(4):p.470-6.
54. Hermine, O., et al., Phase Ⅱ trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J, 2004.5(2):p.130-4.
55. Vuky, J., et al., Phase Ⅱ trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs,2002.20(3):p.327-30.
56. Ravagnan, L., et al., Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene, 1999.18(16):p.2537-46.
57. Gebbia, V., et al., Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer:a phase Ⅱ study of the Southern Italy Oncology Group (GOIM). Anticancer Drugs,1997.8(10):p.943-8.
58. Papaldo, P., et al., Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol,2003. 21(18):p.3462-8.
59. De Lena, M., et al., Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase Ⅱstudy. Eur J Cancer,2001.37(3):p.364-8.
60. Portalone, L., et al., Treatment of inoperable non-small cell lung carcinoma stage Ⅲb and Ⅳ with cisplatin, epidoxorubicin, vindesine and lonidamine:a phase Ⅱ study. Tumori,1999.85(4):p.239-42.
61. De Marinis, F., et al., The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer:a phase Ⅲ randomized FONICAP trial. Italian Lung Cancer Task Force. Tumori,1999. 85(3):p.177-82.
62. Oudard, S., et al., Phase Ⅱ study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol,2003.63(1):p.81-6.
63. Schattner, E.J., Apoptosis in lymphocytic leukemias and lymphomas. Cancer Invest,2002.20(5-6):p.737-48.
64. Selzer, E., et al., Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res,1998. 8(3):p.197-203.
65. Miyashita, T. and J.C. Reed, bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res, 1992.52(19):p.5407-11.
66. Ackermann, E.J., et al., The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem, 1999.274(16):p.11245-52.
67. O'Brien, S., et al., Randomized phase Ⅲ trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol,2007.25(9):p.1114-20.
68. Chanan-Khan, A.A., et al., Phase Ⅲ randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma,2009.50(4):p.559-65.
69. Schimmer, A.D., et al., Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell,2004.5(1):p.25-35.
70. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
71. Yang, L., et al., Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells:implication for cancer specific therapy. Cancer Res,2003.63(20):p.6815-24.
72. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53 network. Nature, 2000.408(6810):p.307-10.
73. Vassilev, L.T., et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science,2004.303(5659):p.844-8.
74. Issaeva, N., et al., Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med,2004.10(12):p. 1321-8.
75. Bykov, V.J., et al., Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med,2002.8(3):p.282-8.
2. Chanan-Khan, A.A., et al., Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma,2009.50(4):p.559-65.
3. Schimmer, A.D., et al., Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell,2004.5(1):p.25-35.
4. Campiglio, M., et al., Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level. J Cell Physiol,2004.198(2):p.259-68.
5. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
6. Ciardiello, F. and G. Tortora, A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clinical Cancer Research, 2001.7(10):p.2958-2970.
7. Webb, A., et al., BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet,1997.349(9059):p.1137-1141.
8. Antonarakis, E.S., M.A. Carducci, and M.A. Eisenberger, Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett, 2010.291(1):p.1-13.
9. Rowinsky, E.K., The erbB family:targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med,2004.55:p.433-57.
10. Yarden, Y. and M.X. Sliwkowski, Untangling the ErbB signalling network. Nat Rev Mol Cell Biol,2001.2(2):p.127-37.
11. Moy, B. and P.E. Goss, Lapatinib:current status and future directions in breast cancer. Oncologist,2006.11(10):p.1047-57.
12. Herbst, R.S. and D.M. Shin, Monoclonal antibodies to target epidermal growth factor receptor-positive tumors:a new paradigm for cancer therapy. Cancer,2002.94(5):p.1593-611.
13. Nahta, R., G.N. Hortobagyi, and F.J. Esteva, Growth factor receptors in breast cancer:potential for therapeutic intervention. Oncologist,2003.8(1):p.5-17.
14. Wood, E.R., et al., A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib):relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res,2004. 64(18):p.6652-9.
15. McArthur, H.,An overview of HER-targeted therapy with lapatinib in breast cancer. Adv Ther,2009.26(3):p.263-71.
16. Nahta, R., et al., Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells:effects on insulin-like growth factor Ⅰ signaling. Mol Cancer Ther, 2007.6(2):p.667-74.
17. Lin, N.U., et al., Multicenter phase Ⅱ study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res,2009.15(4):p. 1452-9.
18. Lin, N.U., et al., Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol,2008.26(12):p.1993-9.
19. Haunstetter, A. and S. Izumo, Apoptosis:basic mechanisms and implications for cardiovascular disease. Circ Res,1998.82(11):p.1111-29.
20. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
21. El-Zawahry, A., J. McKillop, and C. Voelkel-Johnson, Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer,2005.5:p.2.
22. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
23. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
24. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
25. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
26. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
27. Slamon, D.J., et al., Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science,1989.244(4905):p.707-12.
28. Xia, W., et al., Anti-tumor activity of GW572016:a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erkl/2 and AKT pathways. Oncogene,2002.21(41):p.6255-63.
29. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
30. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
31. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
32. Letai, A.G., Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer,2008.8(2):p.121-32.
33. Willis, S.N., et al., Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science,2007.315(5813):p.856-9.
34. Bouillet, P., et al., Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome,2001.12(2): p.163-8.
35. Strasser, A., et al., What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol, 2008.86(1):p.57-66.
36. Marani, M., et al., Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol,2002. 22(11):p.3577-89.
37. Jacobs, F.M., et al., FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem,2003.278(38):p. 35959-67.
38. Tsai, K.L., et al., Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res, 2007.35(20):p.6984-94.
39. Yamamura, Y., et al., RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. J Biol Chem,2006.281(8):p.5267-76.
40. Sunters, A., et al., Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res,2006.66(1):p.212-20.
41. Van Der Heide, L.P., M.F. Hoekman, and M.P. Smidt, The ins and outs of FoxO shuttling:mechanisms of FoxO translocation and transcriptional regulation. Biochem J,2004.380(Pt 2):p.297-309.
42. Li, S., et al., Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther,2007.6(3):p.1031-8.
43. Xia, W., et al., A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A,2006.103(20):p.7795-800.
44. Hegde, P.S., et al., Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther,2007.6(5):p.1629-40.
1. Jemal, A., et al., Cancer statistics,2008. Ca-a Cancer Journal for Clinicians, 2008.58(2):p.71-96.
2. Lowe, S.W. and A.W. Lin, Apoptosis in cancer. Carcinogenesis,2000.21(3):p. 485-95.
3. Nicholson, D.W. and N.A. Thornberry, Apoptosis. Life and death decisions. Science,2003.299(5604):p.214-5.
4. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
5. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
6. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
7. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
8. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
9. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
10. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
11. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
12. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
13. Letai, A.G., Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer,2008.8(2):p.121-32.
14. Willis, S.N., et al., Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science,2007.315(5813):p.856-9.
15. Bouillet, P., et al., Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome,2001.12(2): p.163-8.
16. Strasser, A., et al., What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol, 2008.86(1):p.57-66.
17. Marani, M., et al., Identification of novel isoforms of the BH3 domain protein Bim which directly activate Box to trigger apoptosis. Mol Cell Biol,2002. 22(11):p.3577-89.
18. Lackey, K.E., Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. Curr Top Med Chem,2006.6(5):p.435-60.
19. Xia, W., et al., Anti-tumor activity of GW572016:a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erkl/2 and AKT pathways. Oncogene,2002.21(41):p.6255-63.
20. Xia, W., et al., Regulation of survivin by ErbB2 signaling:therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res,2006. 66(3):p.1640-7.
21. Kopper, L., Lapatinib:a sword with two edges. Pathol Oncol Res,2008.14(1): p.1-8.
22. Oltersdorf, T., et al., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature,2005.435(7042):p.677-81.
23. Chauhan, D., et al., A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene,2007.26(16):p.2374-80.
24. Hann, C.L., et al., Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res,2008.68(7):p.2321-8.
25. Cory, S. and J.M. Adams, Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell,2005.8(1):p.5-6.
26. Chen, S., et al., Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Box translocation. Cancer Res, 2007.67(2):p.782-91.
27. Konopleva, M, et al., Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell,2006. 10(5):p.375-88.
28. Lin, X., et al.,'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene,2007.26(27):p.3972-9.
29. Tahir, S.K., et al., Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res,2007.67(3):p. 1176-83.
30. van Delft, M.F., et al., The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell,2006.10(5):p.389-99.
31. Kang, M.H., et al., Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines:Mcl-1 inactivation. J Natl Cancer Inst,2008.100(8):p.580-95.
32. Del Gaizo Moore, V., et al., Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest,2007.117(1):p.112-21.
33. Berenbaum, M.C., What is synergy? Pharmacol Rev,1989.41(2):p.93-141.
34. Koch, G., et al., Modeling of tumor growth and anticancer effects of combination therapy. J Pharmacokinet Pharmacodyn,2009.36(2):p.179-97.
35. Peterson, J.J., A review of synergy concepts of nonlinear blending and dose-reduction profiles. Front Biosci (Schol Ed),2010.2:p.483-503.
36. Chou, T.C., et al., Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth:a rational approach to clinical protocol design. J Natl Cancer Inst,1994.86(20): p.1517-24.
37. Chou, T.C., Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res,2010.70(2):p.440-6.
38. Cox, E., Synergy in practice:caring for victims of intimate partner violence. Crit Care Nurs Q,2003.26(4):p.323-30.
39. Ferreira, C.G., et al., Apoptosis:target of cancer therapy. Clin Cancer Res, 2002.8(7):p.2024-34.
40. Reed, J.C., Bcl-2 family proteins:regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol,1997.34(4 Suppl 5):p.9-19.
41. Hockenbery, D., et al., Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature,1990.348(6299):p.334-6.
42. Cory, S. and J.M. Adams, The Bcl2 family:regulators of the cellular life-or-death switch. Nat Rev Cancer,2002.2(9):p.647-56.
43. Letai, A., Pharmacological manipulation of Bcl-2 family members to control cell death. J Clin Invest,2005.115(10):p.2648-55.
44. Letai, A., et al., Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell,2004.6(3):p.241-9.
45. Reed, J.C. and M. Pellecchia, Apoptosis-based therapies for hematologic malignancies. Blood,2005.106(2):p.408-18.
46. Adams, J.M. and S. Cory, The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene,2007.26(9):p.1324-37.
47. Zhao, Y, et al., Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci U S A,2005.102(44):p.16090-5.
48. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
49. Tse, C., et al., ABT-263:a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res,2008.68(9):p.3421-8.
50. Cheng, E.H., et al., BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell,2001. 8(3):p.705-11.
51. Kim, H., et al., Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol,2006.8(12):p.1348-58.
52. Letai, A., et al., Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell,2002.2(3):p.183-92.
53. Certo, M., et al., Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell,2006.9(5):p. 351-65.
1. Lowe, S.W. and A.W. Lin, Apoptosis in cancer. Carcinogenesis,2000.21(3):p. 485-95.
2. Hengartner, M.O., The biochemistry of apoptosis. Nature,2000.407(6805):p. 770-6.
3. Hockenbery, D., et al., Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature,1990.348(6299):p.334-6.
4. Zapata, J.M., et al., A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. J Biol Chem,2001.276(26):p. 24242-52.
5. Scaffidi, C., et al., Two CD95 (APO-1/Fas) signaling pathways. EMBO J, 1998.17(6):p.1675-87.
6. Landowski, T.H., et al., CD95 antigen mutations in hematopoietic malignancies. Leuk Lymphoma,2001.42(5):p.835-46.
7. Lamy, T., et al., Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD3(+) large granular lymphocyte leukemia. Blood,1998.92(12):p.4771-7.
8. Tsujimoto, Y., et al., Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome trans location. Science,1984.226(4678):p. 1097-9.
9. Reed, J.C., Bcl-2 family proteins:regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol,1997.34(4 Suppl 5):p.9-19.
10. Curtis, J.R., Life and death decisions in the middle of the night:teaching the assessment of decision-making capacity. Chest,2010.137(2):p.248-50.
11. Reed, J.C., Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ,2006. 13(8):p.1378-86.
12. Green, D.R. and G. Kroemer, The pathophysiology of mitochondrial cell death. Science,2004.305(5684):p.626-9.
13. Huang, D.C. and A. Strasser, BH3-Only proteins-essential initiators of apoptotic cell death. Cell,2000.103(6):p.839-42.
14. Knudson, R., At the gates of life and death. Midwifery Today Int Midwife, 2009(91):p.14-5.
15. Zong, W.X., et al., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 2001.15(12):p.1481-6.
16. Letai, A., BCL-2:found bound and drugged! Trends Mol Med,2005.11(10):p. 442-4.
17. Chen, L., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell,2005. 17(3):p.393-403.
18. Mancini, M., et al., The caspase-3 precursor has a cytosolic and mitochondrial distribution; implications for apoptotic signaling. J Cell Biol, 1998.140(6):p.1485-95.
19. Thornberry, N.A. and Y. Lazebnik, Caspases:enemies within. Science,1998. 281(5381):p.1312-6.
20. Benchimol, S., p53-dependent pathways of apoptosis. Cell Death Differ,2001. 8(11):p.1049-51.
21. Yu, J., et al., Puma mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A,2003.100(4):p.1931-6.
22. Maldonado, V., J. Melendez-Zajgla, and A. Ortega, Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. Mutat Res,1997. 381(1):p.67-75.
23. Kuhnel, F., et al., NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. J Biol Chem,2000.275(9):p. 6421-7.
24. Myung, J., K.B. Kim, and C.M. Crews, The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev,2001.21(4):p.245-73.
25. Wu, W.K., et al., Proteasome inhibition:A new therapeutic strategy to cancer treatment. Cancer Lett,2010.
26. Adams, J., et al., Proteasome inhibitors:a novel class of potent and effective antitumor agents. Cancer Res,1999.59(11):p.2615-22.
27. Hidalgo, M. and E.K. Rowinsky, The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene,2000.19(56):p.6680-6.
28. Cantley, L.C., The phosphoinositide 3-kinase pathway. Science,2002. 296(5573):p.1655-7.
29. Wen, Y., et al., HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res,2000. 60(24):p.6841-5.
30. Cantley, L.C. and B.G. Neel, New insights into tumor suppression:PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A,1999.96(8):p.4240-5.
31. Dancey, J.E., Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am,2002.16(5):p.1101-14.
32. Wang, X., et al., Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem,2000.275(19):p. 14624-31.
33. Tamm, I., F. Schriever, and B. Dorken, Apoptosis:implications of basic research for clinical oncology. Lancet Oncol,2001.2(1):p.33-42.
34. Choi, I.J., et al., Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. Infect Immun,2003.71(2):p.830-7.
35. Liesveld, J.L., et al., Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia,2003.17(9):p.1806-12.
36. Adachi, S., et al., Apoptosis induced by molecular targeting therapy in hematological malignancies. Acta Haematol,2004.111(1-2):p.107-23.
37. Ivy, P.S. and M. Schoenfeldt, Clinical trials referral resource. Current clinical trials of 17-AG and 17-DMAG. Oncology (Williston Park),2004.18(5):p.610, 615,619-20.
38. Mei, S., A.D. Ho, and U. Mahlknecht, Role of histone deacetylase inhibitors in the treatment of cancer (Review). Int J Oncol,2004.25(6):p.1509-19.
39. Campiglio, M., et al., Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level. J Cell Physiol,2004.198(2):p.259-68.
40. Rinehart, J., et al., Multicenter phase Ⅱ study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol,2004.22(22):p.4456-62.
41. Troppmair, J. and U.R. Rapp, Raf and the road to cell survival:a tale of bad spells, ring bearers and detours. Biochem Pharmacol,2003.66(8):p.1341-5.
42. de Vries, E.G., et al., Correspondence re:C. G. Ferreira et al., Apoptosis: target of cancer therapy. Clin. Cancer Res.,8:2024-2034,2002. Clin Cancer Res,2003.9(2):p.912; author reply 913.
43. Tolcher, A.W., Regulators of apoptosis as anticancer targets. Hematol Oncol Clin North Am,2002.16(5):p.1255-67.
44. Havell, E.A., W. Fiers, and R.J. North, The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med,1988.167(3):p.1067-85.
45. Ogasawara, J., et al., Lethal effect of the anti-Fas antibody in mice. Nature, 1993.364(6440):p.806-9.
46. Ferreira, C.G., et al., Apoptosis:target of cancer therapy. Clin Cancer Res, 2002.8(7):p.2024-34.
47. El-Zawahry, A., J. McKillop, and C. Voelkel-Johnson, Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer,2005.5:p.2.
48. Chuntharapai, A., et al., Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol,2001.166(8):p. 4891-8.
49. Plummer, R., et al., Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res,2007.13(20):p.6187-94.
50. Altucci, L., et al., Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med, 2001.7(6):p.680-6.
51. Chou, W.C. and C.V. Dang, Acute promyelocytic leukemia:recent advances in therapy and molecular basis of response to arsenic therapies. Curr Opin Hematol,2005.12(1):p.1-6.
52. Chen, Z., Z.Y. Wang, and S J. Chen, Acute promyelocytic leukemia:cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther,1997. 76(1-3):p.141-9.
53. Hussein, M.A., et al., Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol,2004.125(4):p.470-6.
54. Hermine, O., et al., Phase Ⅱ trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J, 2004.5(2):p.130-4.
55. Vuky, J., et al., Phase Ⅱ trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs,2002.20(3):p.327-30.
56. Ravagnan, L., et al., Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene, 1999.18(16):p.2537-46.
57. Gebbia, V., et al., Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer:a phase Ⅱ study of the Southern Italy Oncology Group (GOIM). Anticancer Drugs,1997.8(10):p.943-8.
58. Papaldo, P., et al., Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol,2003. 21(18):p.3462-8.
59. De Lena, M., et al., Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase Ⅱstudy. Eur J Cancer,2001.37(3):p.364-8.
60. Portalone, L., et al., Treatment of inoperable non-small cell lung carcinoma stage Ⅲb and Ⅳ with cisplatin, epidoxorubicin, vindesine and lonidamine:a phase Ⅱ study. Tumori,1999.85(4):p.239-42.
61. De Marinis, F., et al., The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer:a phase Ⅲ randomized FONICAP trial. Italian Lung Cancer Task Force. Tumori,1999. 85(3):p.177-82.
62. Oudard, S., et al., Phase Ⅱ study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol,2003.63(1):p.81-6.
63. Schattner, E.J., Apoptosis in lymphocytic leukemias and lymphomas. Cancer Invest,2002.20(5-6):p.737-48.
64. Selzer, E., et al., Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res,1998. 8(3):p.197-203.
65. Miyashita, T. and J.C. Reed, bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res, 1992.52(19):p.5407-11.
66. Ackermann, E.J., et al., The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem, 1999.274(16):p.11245-52.
67. O'Brien, S., et al., Randomized phase Ⅲ trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol,2007.25(9):p.1114-20.
68. Chanan-Khan, A.A., et al., Phase Ⅲ randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma,2009.50(4):p.559-65.
69. Schimmer, A.D., et al., Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell,2004.5(1):p.25-35.
70. Bockbrader, K.M., M. Tan, and Y. Sun, A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL-and etoposide-induced apoptosis in breast cancer cells. Oncogene,2005.24(49):p.7381-8.
71. Yang, L., et al., Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells:implication for cancer specific therapy. Cancer Res,2003.63(20):p.6815-24.
72. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53 network. Nature, 2000.408(6810):p.307-10.
73. Vassilev, L.T., et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science,2004.303(5659):p.844-8.
74. Issaeva, N., et al., Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med,2004.10(12):p. 1321-8.
75. Bykov, V.J., et al., Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med,2002.8(3):p.282-8.