苯乙酸对C6胶质瘤细胞凋亡的影响及机制研究
摘要
目的：观察诱导分化剂苯乙酸(PA)对C6胶质瘤细胞凋亡的影响，探讨其作用机制。
方法：通过体外培养C6胶质瘤细胞，给予不同浓度的PA(2.5、5.0和7.5mmol／L)分别诱导分化24、48、72和96h，采用MTT比色法检测PA对C6细胞增殖抑制率，采用显微镜和透射电镜观察细胞形态学变化，流式细胞仪(FCM)和TUNEL检测细胞凋亡，免疫组化或原位杂交检测PA对Bcl-2、Bax、survivin、p53和GFAP表达的影响，激光共聚焦显微镜检测PA对细胞内游离Ca~(2+)浓度的影响。并建立wistar大鼠C6胶质瘤动物模型，腹腔注射PA治疗，研究PA对C6胶质瘤细胞凋亡的影响，检测PA对Bcl-2、Bax、survivin、p53和GFAP表达的影响。
结果：体外实验显示：PA显著抑制C6胶质瘤细胞生长，细胞增殖抑制率随PA浓度和作用时间的增加而增加。在PA作用后，透射电镜观察发现凋亡细胞；FCM和TUNEL检测发现：随PA浓度的增加和作用时间的延长，C6胶质瘤细胞凋亡率增加。免疫组化检测发现PA对Bcl-2、p53和survivin表达没有影响，PA能显著增强GFAP和Bax的表达。原位杂交检测PA对Bcl-2表达没有影响，PA能显著增强Bax的表达。PA作用72h后能明显增加细胞内游离Ca~(2+)浓度，并且随药物浓度的增加而增加，与细胞凋亡率的变化一致。
体内实验显示：实验组的生存时间比对照组明显延长，透射电镜观
Objective: To investigate the effect of differentiation inducer-phenylacetate(PA) on apoptosis in rat C6 glioma cells and to study the mechanisms of PA.
Methods: C6 cells were cultured in vitro. After induced by PA at different concentrations (2.5, 5.0 and 7.5mmol /L) , the rate of cell proliferation inhibition was measured by MTT assay at different time-points(24,48,72 and 96h). The changes of cell morphology was observed by microscope and transmission electron microscope(TEM). Apoptosis was detected by flow cytometry (FCM) with AnnexinV/ propidium iodide(PI) and TUNEL assay. The expression of Bax, Bcl-2, survivin, p53 and GFAP was determined by IC or ISH. The level of intracellular free calcium was determined by laser Confocal scanning microscopy with calcium-flourecent probes-Fluo-3/AM.
Then C6 cells were transplanted into the brain of Wistar rats. PA was administered by peritoneal injection. Apoptosis was detected by TEM and TUNEL. The expression of Bax, Bcl-2, survivin, p53 and GFAP was determined by IC or ISH.
Results: In vitro, the growth of C6 cells was obviously inhibited by PA, and the inhibition rate was increased with the increase of concentration and
方法：通过体外培养C6胶质瘤细胞，给予不同浓度的PA(2.5、5.0和7.5mmol／L)分别诱导分化24、48、72和96h，采用MTT比色法检测PA对C6细胞增殖抑制率，采用显微镜和透射电镜观察细胞形态学变化，流式细胞仪(FCM)和TUNEL检测细胞凋亡，免疫组化或原位杂交检测PA对Bcl-2、Bax、survivin、p53和GFAP表达的影响，激光共聚焦显微镜检测PA对细胞内游离Ca~(2+)浓度的影响。并建立wistar大鼠C6胶质瘤动物模型，腹腔注射PA治疗，研究PA对C6胶质瘤细胞凋亡的影响，检测PA对Bcl-2、Bax、survivin、p53和GFAP表达的影响。
结果：体外实验显示：PA显著抑制C6胶质瘤细胞生长，细胞增殖抑制率随PA浓度和作用时间的增加而增加。在PA作用后，透射电镜观察发现凋亡细胞；FCM和TUNEL检测发现：随PA浓度的增加和作用时间的延长，C6胶质瘤细胞凋亡率增加。免疫组化检测发现PA对Bcl-2、p53和survivin表达没有影响，PA能显著增强GFAP和Bax的表达。原位杂交检测PA对Bcl-2表达没有影响，PA能显著增强Bax的表达。PA作用72h后能明显增加细胞内游离Ca~(2+)浓度，并且随药物浓度的增加而增加，与细胞凋亡率的变化一致。
体内实验显示：实验组的生存时间比对照组明显延长，透射电镜观
Objective: To investigate the effect of differentiation inducer-phenylacetate(PA) on apoptosis in rat C6 glioma cells and to study the mechanisms of PA.
Methods: C6 cells were cultured in vitro. After induced by PA at different concentrations (2.5, 5.0 and 7.5mmol /L) , the rate of cell proliferation inhibition was measured by MTT assay at different time-points(24,48,72 and 96h). The changes of cell morphology was observed by microscope and transmission electron microscope(TEM). Apoptosis was detected by flow cytometry (FCM) with AnnexinV/ propidium iodide(PI) and TUNEL assay. The expression of Bax, Bcl-2, survivin, p53 and GFAP was determined by IC or ISH. The level of intracellular free calcium was determined by laser Confocal scanning microscopy with calcium-flourecent probes-Fluo-3/AM.
Then C6 cells were transplanted into the brain of Wistar rats. PA was administered by peritoneal injection. Apoptosis was detected by TEM and TUNEL. The expression of Bax, Bcl-2, survivin, p53 and GFAP was determined by IC or ISH.
Results: In vitro, the growth of C6 cells was obviously inhibited by PA, and the inhibition rate was increased with the increase of concentration and
引文
1．王忠诚．颅内肿瘤总论．见：王忠诚主编．神经外科学．第1版．武汉：湖北科技出版社，1998：397．
2. Reni M, Mazza E, Tosoni A, et al. Novel therapeutics in adult malignant brain gliomas. Expert Opin Investig Drugs, 2005, 14 (6) : 643-658.
3．陈忠平，周旺宁．我国胶质瘤诊断治疗现状和努力方向．中国肿瘤，2005，14 (2)：78-81．
4. Neish W. Phenylacetic acid as a potential therapeutic agent for the treatment of human cancer. Esperientia (Basel), 1971, 27: 860-864.
5. Samid D, Shack S, Sherman LT, et al. Phenylacetate: A Novel Nontoxic Inducer of Tumor Cell Differentiation. Cancer Res, 1992, 52: 1988-1992.
6. Samid D, Shack S, Myers CE, et al. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J Clin Invest, 1993, 91: 2288-2295.
7. Samid D, Ram Z, Hudgins WR, et al. Selective activity of phenylacetate against malignant gliomas: Resemblance to fetal brain damage in phenylketonuria. Cancer Res, 1994, 54 (4) : 891-895.
8. Ferrandina G, Filippini P, Ferlini C, et al. Growth inhibitory effects and radiosensitization induced by fatty aromatic acids on human cervical cancer cells. Oncol Res, 2000, 12 (9-10) : 429-440.
9. Vasse M, Thibout D, Paysant J, et al. Decrease of breast cancer cell invasiveness by sodium phenylacetate (NaPa) is associated with an increased expression of adhesive molecules. Br J Cancer, 2001, 84 (6) : 802-807.
10. Franco OE, Onishi T, Umeda Y, et al. Phenylacetate inhibits growth and modulates cell cycle gene expression in renal cancer cell lines. Anticancer Res, 2003, 23 (2B) : 1637-1642.
11．张莉，李清泉．苯乙酸钠抗癌机制研究进展．国外医学肿瘤学分册，2004，31(5)：365-368．
12. Samid D, Hudgins WR, Shack S, et al. Phenylacetate and phenybutyrate as novel, nontoxic differentiation inducers. Ads Exp Med Biol, 1997, 400: 501-505.
13．田宇，陈宝琴，赵丛海，等．苯乙酸对胶质瘤细胞G1期增殖抑制作用．中华肿瘤杂志，2000，22；213-214．
14．杨朝华，田宇，卜丽莎，等．同源盒基因在胶质瘤细胞中的表达．中国肿瘤临床，2002，29 (6)：418-420．
15. Schmidt F, Groscurth P, Kermer M, et al. Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells. Acta Neuropathol (Berl), 2001, 101 (3) : 217-224.
16. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther, 2005, 12 (4) : 585-598.
17. Vertosick FT Jr, Selker RG, Arena VC. Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery, 1991, 28 (4) : 496-501.
18. Soffietti R, Chio A, Giordana MT, et al. Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery, 1989 24 (5) : 686-692.
19. Sachs L. Control of normal differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature, 1978, 274: 535-539.
20. Sanz MA, Martin G, Diaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med, 1998, 338: 393-394.
21. Chang SM, Kuhn JG, Ian Robins H, et al. A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors consortium report. Invest New Drugs, 2003, 21 (4) : 429-433.
22. Stockhammer G, Manley GT, Johnson S, et al. Inhibition of proliferation and induction of differntiation in medulloblastoma-and astrocytoma-derived cell lines with phenylacetate. J Neurosurg, 1995; 83; 672-681.
23. Cosentini E, Haberl I, Pertschy P, et al. The differentiation inducers phenylacetate and phenylbutyrate modulate camptothecin sensitivity in colon carcinoma cells in vitro by intracellular acidification. Int J Oncol, 2001, 19 (5) : 1069-1074.
24．彭黎明．六种细胞凋亡检测方法的比较．中华病理学杂志，1999，28(1)：55-57．
25. Carducci MA, Nelson JB, Chan-Tack KM, et al. Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res, 1996, 2 (2) : 379-387.
26. Witzig TE, Timm M, Stenson M, et al. Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin Cancer Res, 2000, 6 (2) : 681-692.
27. Li XN, Parikh S, Shu Q, et al. Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells. Clin Cancer Res, 2004, 10(3): 1150-1159.
28.Steinbach JP, Weller M. Apoptosis in gliomas: molecular mechanisms and therapeutic implications. J Neurooncol, 2004 ,70(2):245-254.
29.Reed JC. Mechanisms of Apoptosis. American Journal of Pathology, 2000,157:1415-1430.
30.Pan G, O'Rourke K, Dixit VM. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem, 1998, 273(10):5841-5845.
31.Hegde R, Srinivasula SM, Ahmad M, et al. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J Biol Chem, 1998, 273(14):7783-7786.
32.Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the Bcl-2 family and cell death. Blood, 1996, 88(2):386-401.
33. Bougras G, Cartron PF, Gautier F, et al. Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system. BMC Cancer, 2004, 4(1):54.
34. Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell, 1995, 80(2):293-299.
35. Onishi T, Yamakawa K, Franco OE, et al. p27Kipl is the key mediator of phenylacetate induced cell cycle arrest in human prostate cancer cells. Anticancer Res, 2000,20(5A):3075-3081.
36. Tamm I, Wang Y, Sausville E, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas(CD59), Bax, caspases, and anticancer drugs . Cancer Res, 1998,58 :5315-5320
37.Lu CD, Altieri DC, Tanigawa N, et al.Expression of a novel antiapoptosis gene ,survivin,correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res, 1998, 58 (9) : 1808-1812.
38. Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 2002, 21 (17) : 2613-2622.
39. Das A, Tan WL, Teo J, et al. Expression of survivin in primary glioblastomas. J Cancer Res Clin Oncol, 2002, 128 (6) : 302-306.
40. Uchida H, Tanaka T, Sasaki K, et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther, 2004, 10 (1) : 162-171.
41. Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-retculum-specific apoptosis and cytotoxicity amyloid-beta. Nature, 2000; 403 (6765) : 98-103.
42. Mcconkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. Leukoc Biol, 1996; 59 (6) : 775-783.
43. Zhang W, Couldwell WT, Song H, et al. Tamoxifen-induced enhancement of calcium signaling in glioma and MCF-7 breast cancer cells. Cancer Res, 2000; 60 (19) : 5395-5400.
44. Qi H, Chen HZ, Jin ZJ. Caspase 3 gene expression and [Ca2+]i homeostasis underlying desipramine-induced C6 glioma cell apoptosis. Acta Pharmacol Sin, 2002; 23 (9) : 803-807.
45．江玉泉，李冰，姜政，等．组胺诱导胶质瘤原代培养细胞凋亡的实验研究．中华神经外科杂志，2005，21(5)：265-26
46. Mishra DP, Pal R, Shaha C. Changes in cytosolic Ca2+ levels regulate Bcl-xS and Bcl-xL expression in spermatogenic cells during apoptotic death. J Biol Chem, 2006, 281 (4) : 2133-2143.
1. Barth RF. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol, 1998, 36 (1) : 91-102.
2. Dai C, Holland EC. Glioma Models. Biochim Biophys Acta, 2001, 1551 (1) : M19-27.
3. Peterson DL, Sheridan PJ, Brown WE Jr. Animal models for brain tumors: historical perspectives and future directions. J Neurosurg, 1994, 80 (5) : 865-876.
4. San-Galli F, Vrignaud P, Robert J, et al. Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J Neurooncol, 1989, 7 (3) : 299-304.
5．王晓刚，魏学忠，周定标．Wstar大鼠C6胶质瘤动物模型的肿瘤生长特点．军医进修学院学报，2001，22 (4)：300-303．
6．姬西团，章翔，费舟，等．颅内胶质瘤模型建立及肿瘤生长特征观察．中华神经外科疾病研究杂志，2004，3 (1)：4-8．
7．赵澎，张亚卓．鼠胶质瘤动物模型的建立及应用．国外医学神经病学神经外科学分册，2005，32(1)：38-41．
8. Shack S, Miller A, Liu L, et al. Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate. Clin Cancer Res, 1996, 2 (5) : 865-872.
9．王重韧，黄强．脂肪酸类药物诱导分化治疗脑胶质瘤分子机制研究．中华神经医学杂志，2005，4(2)；197-200．
10. Piscitelli SC, Thibault A, Figg WD, et al. Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol, 1995, 35 (4) : 368-373.
11. Berg S, Serabe B, Aleksic A, et al. Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. Cancer Chemother Pharmacol, 2001, 47 (5) : 385-390.
12. Chang SM, Kuhn JG, Robins HI, et al. Phase Ⅱ study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol, 1999, 17 (3) : 984-990.
13. Cardoso RC, Lobao-Soares B, Bianchin MM, et al. Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model. BMC Neurosci, 2004, 5 (1) : 38.
14．田宇，陈阳，刘冰，等．苯乙酸、二甲基甲酰胺对胶质瘤细胞基因蛋白水平表达的影响及意义．中国肿瘤临床，2001，28(2)：125-128．
15. Xie D, Zeng YX, Wang HJ, et al. Expression of cytoplasmic and nuclear Survivin in primary and secondary human glioblastoma. Br J Cancer, 2006, 94 (1) : 108-114.
16．刘青华，李灵敏，王晋芬．p53相关基因与脑胶质瘤．肿瘤研究与临床，2005，17 (1)：65-67．
17. Ito H, Kanzawa T, Kondo S, et al. Microtubule inhibitor D-24851 induces p53-independent apoptotic cell death in malignant glioma cells through Bcl-2 phosphorylation and Bax translocation. Int J Oncol, 2005, 26 (3) : 589-596.
18. Lytle RA, Jiang Z, Zheng X, et al. BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells. J Neurooncol, 2004, 68 (3) : 233-241.
19. Ozawa T, Hu JL, Hu LJ, et al. Functionality of hypoxia-induced BAX expression in a human glioblastoma xenograft model. Cancer Gene Ther, 2005, 12 (5) : 449-455.
20. Adam L, Crepin M, Israel L. Tumor growth inhibition, apoptosis, and Bcl-2 down-regulation of MCF-7ras tumors by sodium phenylacetate and tamoxifen combination. Cancer Res, 1997, 57 (6) : 1023-1029.
21. Ferrandina G, Melichar B, Loercher A, et al. Growth inhibitory effects of sodium phenylacetate (NSC 3039) on ovarian carcinoma cells in vitro. Cancer Res, 1997, 57 (19) : 4309-4315.
22．叶炯贤，吴军，关志枕，等．苯乙酸钠诱导人前列腺癌细胞凋亡及其机理的研究．中国老年学杂志，2003，23 (11)：764-766．
23. Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol, 2005, 23 (10) : 2411-2422.
24. Gerl R, Vaux DL. Apoptosis in the development and treatment of cancer. Carcinogenesis, 2005, 26 (2) : 263-270.
25. Bogler O, Mikkelsen T. Angiogenesis and apoptosis in glioma: two arenas for promising new therapies. J Cell Biochem, 2005, ; 96 (1) : 16-24.
1. Reni M, Mazza E, Tosoni A, et al. Novel therapeutics in adult malignant brain gliomas. Expert Opin Investig Drugs, 2005, 14 (6) : 643-658.
2．陈忠平，周旺宁．我国胶质瘤诊断治疗现状和努力方向．中国肿瘤，2005，14 (2)：78-81．
3. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther, 2005, 12 (4) : 585-598.
4. Vertosick FT Jr, Selker RG, Arena VC. Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery, 1991, 28 (4) : 496-501.
5. Soffietti R, Chio A, Giordana MT, et al. Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery, 1989, 24 (5) : 686-692.
6. Sachs L. Control of normal differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature, 1978, 274: 535-539.
7. Sanz MA, Martin G, Diaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med, 1998, 338: 393-394.
8. Li XN, Du ZW, Huang Q. Modulation effects of hexamethylene bisacetamide on growth and differentiation of cultured human malignant glioma cells J. J Neurosurg, 1996, 84 (5) : 831-838.
9. Li XN, Du ZW, Huang Q, et al. Growth-inhibitory and differentiation-inducing activity of dimethylformamide in cultured human malignant glioma cells. Neurosurgery, 1997, 40 (6) : 1250-1258.
10．田宇，陈阳，刘冰，等．苯乙酸、二甲基甲酞胺对胶质瘤细胞基因蛋白水平表达的影响及意义．中国肿瘤临床，2001，28(2)：125-128
11. Rutka JT, De Armond SJ, Giblin J, et al. Effect of retinoids on the proliferation, morphology and expression of glial fibrillary acidic protein of an anaplastic astrocytoma cell line. Int J Cancer, 1988,42(3):419-427.
12.Steck PA, Hadi A, Lotan R, et al. Inhibition of epidermal growth factor receptor activity by retinoic acid in glioma cells. J Cell Biochem, 1990 , 42(2):83-94.
13.Westarp ME, Westarp MP, Grundl W, et al. Improving medical approaches to primary CNS malignancies--retinoid therapy and more. Med Hypotheses,1993,41(3):267-276.
14.Defer GL, Adle-Biassette H, Ricolfi F, et al. All-trans retinoic acid in relapsing malignant gliomas: clinical and radiological stabilization associated with the appearance of intratumoral calcifications. J Neurooncol, 1997, 34(2): 169-177.
15.Stockhammer G, Manley GT, Johnson R, et al. Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate. J Neurosurg, 1995,83(4):672-681.
16.Samid D, Ram Z, Hudgins WR, et al. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res, 1994 ,54(4):891-895.
17.Ram Z, Samid D, Walbridge S, et al. Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate. Cancer Res, 1994, 54(11):2923-2927.
18. Engelhard HH, Homer RJ, Duncan HA, et al. Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells. J Neurooncol, 1998, 37 (2) : 97-108.
19. Li XN, Parikh S, Shu Q, et al. Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells. Clin Cancer Res, 2004, 10 (3) : 1150-1159.
20. Lin YH, Chiu JH, Tseng WS, et al. Antiproliferation and radiosensitization of caffeic acid phenethyl ester on human medulloblastoma cells. Cancer Chemother Pharmacol, 2006, 57 (4) : 525-532.
21. Chang SM, Kuhn JG, Robins HI, et al. Phase Ⅱ study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol, 1999, 17 (3) : 984-990.
22. Chang SM, Kuhn JG, Ian Robins H, et al. A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors consortium report. Invest New Drugs, 2003, 21 (4) : 429-433.
23. Tsai CH, Hung LM, Cheng HP, et al. Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors. J Neurooncol, 1995, 23 (1) : 41-52.
24. Tanaka S, Nagashima T, Manaka S, et al. Growth suppression and astrocytic differentiation of glioma cells by interleukin-1. J Neurosurg, 1994, 81 (3) : 402-410.
25．周洪语，侯菊生，罗其中．榄香烯抗肿瘤作用机制的研究进展．中国肿瘤临床，2000，27(5)：392-394．
26. Miller AC, Whittaker T, Thibault A, et al. Modulation of radiation response of human tumour cells by the differentiation inducers, phenylacetate and phenylbutyrate. Int J Radiat Biol, 1997 ,72(2):211-218.
27.Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature, 2004, 432(7015):396-401.
1.Reed JC. Mechanisms of Apoptosis. American Journal of Pathology, 2000, 157:1415-1430.
2. Minn AJ, Velez P, Schendel SL, et al. Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature, 1997, 385(6614):353-357.
3. Pan G, O'Rourke K, Dixit VM. Caspase-9,Bcl-XL,and Apaf-1 form a ternary complex. J Biol Chem, 1998, 273(10):5841-5845.
4. Hegde R, Srinivasula SM, Ahmad M, et al. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J Biol Chem, 1998, 273(14):7783-7786.
5.Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the Bcl-2 family and cell death. Blood, 1996, 88(2):386-401.
6. Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell, 1995, 80(2):293-299.
7. Suzuki A, Ito T, Kawano H, et al. Survivn initiates ptrocaspase 3/ p21 complex formation as a result of interaction with CDK4 to resist Fas-mediated cell death. Oncogene, 2000, 19(10): 1346-1353.
8. Shankar SL, Mani S, O'Guin KN, et al. Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways. J Neurochem, 2001, 79(2):426-436.
9. Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 2002, 21(17):2613-2622.
10. Martin S, Toquet C, Oliver L, et al. Expression of Bcl-2, Bax and bcl-xl in human gliomas: a re-appraisal. J Neurooncol, 2001, 52(2): 129-139.
11. Cartron PF, Oliver L, Martin S, et al. The expression of a new variant of the pro-apoptotic molecule Bax, Baxpsi, is correlated with an increased survival of glioblastoma multiforme patients. Hum Mol Genet, 2002, 11:675-687.
12. Bougras G, Cartron PF, Gautier F, et al. Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system. BMC Cancer, 2004, 4(1):54.
13. Kaliberov S, Stackhouse MA, Kaliberova L, et al. Enhanced apoptosis following treatment with TRA-8 anti-human DR5 monoclonal antibody and overexpression of exogenous Bax in human glioma cells. Gene Ther, 2004, 11(8):658-667.
14. Sasaki T, Lopes MB, Hankins GR, et al. Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. Acta Neuropathol (Berl), 2002, 104(1): 105-109.
15. Chakravarti A, Noll E, Black PM, et al. Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol, 2002, 20(4): 1063-1068.
16. Das A, Tan WL, Teo J, et al. Expression of survivin in primary glioblastomas. J Cancer Res Clin Oncol, 2002,128(6):302-306.
17. Chiou SK, Jones MK, Tarnawski AS. Survivin--an antiapopotosis protein: its biological roles and implications for cancer and beyond. Med Sci Monit, 2003, 9(4):125-129.
18. Uchida H, Tanaka T, Sasaki K, et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther, 2004, 10(1): 162-171.
19. Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol, 1999, 187:127-137.
20. Winter S, Weller M. Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan invovles inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. J Pharmacol Exp Ther, 1998, 286(3) :1374-1382.
21.Roth W, Wagenknecht B, Crimmel C, et al. Taxol-mediated augmentation of CD95 Ligand-induced apoptosis of human malignant glioma cells:association with Bcl-2 phosphorylation but neither a ctivation of p53 nor G2/ M cell cycle arrest. Br J Cancer, 1998, 77(3):404-411.
22. Meng RD, Phillips P. E1-Deiry-ws, P53-independent increase in E2F-2 expression enhances the cytotoxic effects of etoposide and of adriamycin. Int J Oncol, 1999,14(1):5-14.
23. Lytle RA, Jiang Z, Zheng X, et al. BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells. J Neurooncol, 2004, 68(3):233-241.
24. Zartman JK, Foreman NK, Donson AM, et al. Measurement of tamoxifen-induced apoptosis in glioblastoma by cytometric bead analysis of active caspase-3. J Neurooncol, 2004, 67(1-2):3-7.
25.Jiang Z, Zheng X, Lytle RA, et al. Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. J Neurochem, 2004, 89(1):168-178.
2. Reni M, Mazza E, Tosoni A, et al. Novel therapeutics in adult malignant brain gliomas. Expert Opin Investig Drugs, 2005, 14 (6) : 643-658.
3．陈忠平，周旺宁．我国胶质瘤诊断治疗现状和努力方向．中国肿瘤，2005，14 (2)：78-81．
4. Neish W. Phenylacetic acid as a potential therapeutic agent for the treatment of human cancer. Esperientia (Basel), 1971, 27: 860-864.
5. Samid D, Shack S, Sherman LT, et al. Phenylacetate: A Novel Nontoxic Inducer of Tumor Cell Differentiation. Cancer Res, 1992, 52: 1988-1992.
6. Samid D, Shack S, Myers CE, et al. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J Clin Invest, 1993, 91: 2288-2295.
7. Samid D, Ram Z, Hudgins WR, et al. Selective activity of phenylacetate against malignant gliomas: Resemblance to fetal brain damage in phenylketonuria. Cancer Res, 1994, 54 (4) : 891-895.
8. Ferrandina G, Filippini P, Ferlini C, et al. Growth inhibitory effects and radiosensitization induced by fatty aromatic acids on human cervical cancer cells. Oncol Res, 2000, 12 (9-10) : 429-440.
9. Vasse M, Thibout D, Paysant J, et al. Decrease of breast cancer cell invasiveness by sodium phenylacetate (NaPa) is associated with an increased expression of adhesive molecules. Br J Cancer, 2001, 84 (6) : 802-807.
10. Franco OE, Onishi T, Umeda Y, et al. Phenylacetate inhibits growth and modulates cell cycle gene expression in renal cancer cell lines. Anticancer Res, 2003, 23 (2B) : 1637-1642.
11．张莉，李清泉．苯乙酸钠抗癌机制研究进展．国外医学肿瘤学分册，2004，31(5)：365-368．
12. Samid D, Hudgins WR, Shack S, et al. Phenylacetate and phenybutyrate as novel, nontoxic differentiation inducers. Ads Exp Med Biol, 1997, 400: 501-505.
13．田宇，陈宝琴，赵丛海，等．苯乙酸对胶质瘤细胞G1期增殖抑制作用．中华肿瘤杂志，2000，22；213-214．
14．杨朝华，田宇，卜丽莎，等．同源盒基因在胶质瘤细胞中的表达．中国肿瘤临床，2002，29 (6)：418-420．
15. Schmidt F, Groscurth P, Kermer M, et al. Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells. Acta Neuropathol (Berl), 2001, 101 (3) : 217-224.
16. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther, 2005, 12 (4) : 585-598.
17. Vertosick FT Jr, Selker RG, Arena VC. Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery, 1991, 28 (4) : 496-501.
18. Soffietti R, Chio A, Giordana MT, et al. Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery, 1989 24 (5) : 686-692.
19. Sachs L. Control of normal differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature, 1978, 274: 535-539.
20. Sanz MA, Martin G, Diaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med, 1998, 338: 393-394.
21. Chang SM, Kuhn JG, Ian Robins H, et al. A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors consortium report. Invest New Drugs, 2003, 21 (4) : 429-433.
22. Stockhammer G, Manley GT, Johnson S, et al. Inhibition of proliferation and induction of differntiation in medulloblastoma-and astrocytoma-derived cell lines with phenylacetate. J Neurosurg, 1995; 83; 672-681.
23. Cosentini E, Haberl I, Pertschy P, et al. The differentiation inducers phenylacetate and phenylbutyrate modulate camptothecin sensitivity in colon carcinoma cells in vitro by intracellular acidification. Int J Oncol, 2001, 19 (5) : 1069-1074.
24．彭黎明．六种细胞凋亡检测方法的比较．中华病理学杂志，1999，28(1)：55-57．
25. Carducci MA, Nelson JB, Chan-Tack KM, et al. Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res, 1996, 2 (2) : 379-387.
26. Witzig TE, Timm M, Stenson M, et al. Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin Cancer Res, 2000, 6 (2) : 681-692.
27. Li XN, Parikh S, Shu Q, et al. Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells. Clin Cancer Res, 2004, 10(3): 1150-1159.
28.Steinbach JP, Weller M. Apoptosis in gliomas: molecular mechanisms and therapeutic implications. J Neurooncol, 2004 ,70(2):245-254.
29.Reed JC. Mechanisms of Apoptosis. American Journal of Pathology, 2000,157:1415-1430.
30.Pan G, O'Rourke K, Dixit VM. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem, 1998, 273(10):5841-5845.
31.Hegde R, Srinivasula SM, Ahmad M, et al. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J Biol Chem, 1998, 273(14):7783-7786.
32.Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the Bcl-2 family and cell death. Blood, 1996, 88(2):386-401.
33. Bougras G, Cartron PF, Gautier F, et al. Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system. BMC Cancer, 2004, 4(1):54.
34. Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell, 1995, 80(2):293-299.
35. Onishi T, Yamakawa K, Franco OE, et al. p27Kipl is the key mediator of phenylacetate induced cell cycle arrest in human prostate cancer cells. Anticancer Res, 2000,20(5A):3075-3081.
36. Tamm I, Wang Y, Sausville E, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas(CD59), Bax, caspases, and anticancer drugs . Cancer Res, 1998,58 :5315-5320
37.Lu CD, Altieri DC, Tanigawa N, et al.Expression of a novel antiapoptosis gene ,survivin,correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res, 1998, 58 (9) : 1808-1812.
38. Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 2002, 21 (17) : 2613-2622.
39. Das A, Tan WL, Teo J, et al. Expression of survivin in primary glioblastomas. J Cancer Res Clin Oncol, 2002, 128 (6) : 302-306.
40. Uchida H, Tanaka T, Sasaki K, et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther, 2004, 10 (1) : 162-171.
41. Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-retculum-specific apoptosis and cytotoxicity amyloid-beta. Nature, 2000; 403 (6765) : 98-103.
42. Mcconkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. Leukoc Biol, 1996; 59 (6) : 775-783.
43. Zhang W, Couldwell WT, Song H, et al. Tamoxifen-induced enhancement of calcium signaling in glioma and MCF-7 breast cancer cells. Cancer Res, 2000; 60 (19) : 5395-5400.
44. Qi H, Chen HZ, Jin ZJ. Caspase 3 gene expression and [Ca2+]i homeostasis underlying desipramine-induced C6 glioma cell apoptosis. Acta Pharmacol Sin, 2002; 23 (9) : 803-807.
45．江玉泉，李冰，姜政，等．组胺诱导胶质瘤原代培养细胞凋亡的实验研究．中华神经外科杂志，2005，21(5)：265-26
46. Mishra DP, Pal R, Shaha C. Changes in cytosolic Ca2+ levels regulate Bcl-xS and Bcl-xL expression in spermatogenic cells during apoptotic death. J Biol Chem, 2006, 281 (4) : 2133-2143.
1. Barth RF. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol, 1998, 36 (1) : 91-102.
2. Dai C, Holland EC. Glioma Models. Biochim Biophys Acta, 2001, 1551 (1) : M19-27.
3. Peterson DL, Sheridan PJ, Brown WE Jr. Animal models for brain tumors: historical perspectives and future directions. J Neurosurg, 1994, 80 (5) : 865-876.
4. San-Galli F, Vrignaud P, Robert J, et al. Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J Neurooncol, 1989, 7 (3) : 299-304.
5．王晓刚，魏学忠，周定标．Wstar大鼠C6胶质瘤动物模型的肿瘤生长特点．军医进修学院学报，2001，22 (4)：300-303．
6．姬西团，章翔，费舟，等．颅内胶质瘤模型建立及肿瘤生长特征观察．中华神经外科疾病研究杂志，2004，3 (1)：4-8．
7．赵澎，张亚卓．鼠胶质瘤动物模型的建立及应用．国外医学神经病学神经外科学分册，2005，32(1)：38-41．
8. Shack S, Miller A, Liu L, et al. Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate. Clin Cancer Res, 1996, 2 (5) : 865-872.
9．王重韧，黄强．脂肪酸类药物诱导分化治疗脑胶质瘤分子机制研究．中华神经医学杂志，2005，4(2)；197-200．
10. Piscitelli SC, Thibault A, Figg WD, et al. Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol, 1995, 35 (4) : 368-373.
11. Berg S, Serabe B, Aleksic A, et al. Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. Cancer Chemother Pharmacol, 2001, 47 (5) : 385-390.
12. Chang SM, Kuhn JG, Robins HI, et al. Phase Ⅱ study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol, 1999, 17 (3) : 984-990.
13. Cardoso RC, Lobao-Soares B, Bianchin MM, et al. Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK, a metabolically resistant bradykinin B1 agonist, in a rat C6 glioma model. BMC Neurosci, 2004, 5 (1) : 38.
14．田宇，陈阳，刘冰，等．苯乙酸、二甲基甲酰胺对胶质瘤细胞基因蛋白水平表达的影响及意义．中国肿瘤临床，2001，28(2)：125-128．
15. Xie D, Zeng YX, Wang HJ, et al. Expression of cytoplasmic and nuclear Survivin in primary and secondary human glioblastoma. Br J Cancer, 2006, 94 (1) : 108-114.
16．刘青华，李灵敏，王晋芬．p53相关基因与脑胶质瘤．肿瘤研究与临床，2005，17 (1)：65-67．
17. Ito H, Kanzawa T, Kondo S, et al. Microtubule inhibitor D-24851 induces p53-independent apoptotic cell death in malignant glioma cells through Bcl-2 phosphorylation and Bax translocation. Int J Oncol, 2005, 26 (3) : 589-596.
18. Lytle RA, Jiang Z, Zheng X, et al. BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells. J Neurooncol, 2004, 68 (3) : 233-241.
19. Ozawa T, Hu JL, Hu LJ, et al. Functionality of hypoxia-induced BAX expression in a human glioblastoma xenograft model. Cancer Gene Ther, 2005, 12 (5) : 449-455.
20. Adam L, Crepin M, Israel L. Tumor growth inhibition, apoptosis, and Bcl-2 down-regulation of MCF-7ras tumors by sodium phenylacetate and tamoxifen combination. Cancer Res, 1997, 57 (6) : 1023-1029.
21. Ferrandina G, Melichar B, Loercher A, et al. Growth inhibitory effects of sodium phenylacetate (NSC 3039) on ovarian carcinoma cells in vitro. Cancer Res, 1997, 57 (19) : 4309-4315.
22．叶炯贤，吴军，关志枕，等．苯乙酸钠诱导人前列腺癌细胞凋亡及其机理的研究．中国老年学杂志，2003，23 (11)：764-766．
23. Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol, 2005, 23 (10) : 2411-2422.
24. Gerl R, Vaux DL. Apoptosis in the development and treatment of cancer. Carcinogenesis, 2005, 26 (2) : 263-270.
25. Bogler O, Mikkelsen T. Angiogenesis and apoptosis in glioma: two arenas for promising new therapies. J Cell Biochem, 2005, ; 96 (1) : 16-24.
1. Reni M, Mazza E, Tosoni A, et al. Novel therapeutics in adult malignant brain gliomas. Expert Opin Investig Drugs, 2005, 14 (6) : 643-658.
2．陈忠平，周旺宁．我国胶质瘤诊断治疗现状和努力方向．中国肿瘤，2005，14 (2)：78-81．
3. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther, 2005, 12 (4) : 585-598.
4. Vertosick FT Jr, Selker RG, Arena VC. Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography. Neurosurgery, 1991, 28 (4) : 496-501.
5. Soffietti R, Chio A, Giordana MT, et al. Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery, 1989, 24 (5) : 686-692.
6. Sachs L. Control of normal differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature, 1978, 274: 535-539.
7. Sanz MA, Martin G, Diaz-Mediavilla J. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med, 1998, 338: 393-394.
8. Li XN, Du ZW, Huang Q. Modulation effects of hexamethylene bisacetamide on growth and differentiation of cultured human malignant glioma cells J. J Neurosurg, 1996, 84 (5) : 831-838.
9. Li XN, Du ZW, Huang Q, et al. Growth-inhibitory and differentiation-inducing activity of dimethylformamide in cultured human malignant glioma cells. Neurosurgery, 1997, 40 (6) : 1250-1258.
10．田宇，陈阳，刘冰，等．苯乙酸、二甲基甲酞胺对胶质瘤细胞基因蛋白水平表达的影响及意义．中国肿瘤临床，2001，28(2)：125-128
11. Rutka JT, De Armond SJ, Giblin J, et al. Effect of retinoids on the proliferation, morphology and expression of glial fibrillary acidic protein of an anaplastic astrocytoma cell line. Int J Cancer, 1988,42(3):419-427.
12.Steck PA, Hadi A, Lotan R, et al. Inhibition of epidermal growth factor receptor activity by retinoic acid in glioma cells. J Cell Biochem, 1990 , 42(2):83-94.
13.Westarp ME, Westarp MP, Grundl W, et al. Improving medical approaches to primary CNS malignancies--retinoid therapy and more. Med Hypotheses,1993,41(3):267-276.
14.Defer GL, Adle-Biassette H, Ricolfi F, et al. All-trans retinoic acid in relapsing malignant gliomas: clinical and radiological stabilization associated with the appearance of intratumoral calcifications. J Neurooncol, 1997, 34(2): 169-177.
15.Stockhammer G, Manley GT, Johnson R, et al. Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate. J Neurosurg, 1995,83(4):672-681.
16.Samid D, Ram Z, Hudgins WR, et al. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res, 1994 ,54(4):891-895.
17.Ram Z, Samid D, Walbridge S, et al. Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate. Cancer Res, 1994, 54(11):2923-2927.
18. Engelhard HH, Homer RJ, Duncan HA, et al. Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells. J Neurooncol, 1998, 37 (2) : 97-108.
19. Li XN, Parikh S, Shu Q, et al. Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells. Clin Cancer Res, 2004, 10 (3) : 1150-1159.
20. Lin YH, Chiu JH, Tseng WS, et al. Antiproliferation and radiosensitization of caffeic acid phenethyl ester on human medulloblastoma cells. Cancer Chemother Pharmacol, 2006, 57 (4) : 525-532.
21. Chang SM, Kuhn JG, Robins HI, et al. Phase Ⅱ study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol, 1999, 17 (3) : 984-990.
22. Chang SM, Kuhn JG, Ian Robins H, et al. A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors consortium report. Invest New Drugs, 2003, 21 (4) : 429-433.
23. Tsai CH, Hung LM, Cheng HP, et al. Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors. J Neurooncol, 1995, 23 (1) : 41-52.
24. Tanaka S, Nagashima T, Manaka S, et al. Growth suppression and astrocytic differentiation of glioma cells by interleukin-1. J Neurosurg, 1994, 81 (3) : 402-410.
25．周洪语，侯菊生，罗其中．榄香烯抗肿瘤作用机制的研究进展．中国肿瘤临床，2000，27(5)：392-394．
26. Miller AC, Whittaker T, Thibault A, et al. Modulation of radiation response of human tumour cells by the differentiation inducers, phenylacetate and phenylbutyrate. Int J Radiat Biol, 1997 ,72(2):211-218.
27.Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature, 2004, 432(7015):396-401.
1.Reed JC. Mechanisms of Apoptosis. American Journal of Pathology, 2000, 157:1415-1430.
2. Minn AJ, Velez P, Schendel SL, et al. Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature, 1997, 385(6614):353-357.
3. Pan G, O'Rourke K, Dixit VM. Caspase-9,Bcl-XL,and Apaf-1 form a ternary complex. J Biol Chem, 1998, 273(10):5841-5845.
4. Hegde R, Srinivasula SM, Ahmad M, et al. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J Biol Chem, 1998, 273(14):7783-7786.
5.Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the Bcl-2 family and cell death. Blood, 1996, 88(2):386-401.
6. Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell, 1995, 80(2):293-299.
7. Suzuki A, Ito T, Kawano H, et al. Survivn initiates ptrocaspase 3/ p21 complex formation as a result of interaction with CDK4 to resist Fas-mediated cell death. Oncogene, 2000, 19(10): 1346-1353.
8. Shankar SL, Mani S, O'Guin KN, et al. Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways. J Neurochem, 2001, 79(2):426-436.
9. Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 2002, 21(17):2613-2622.
10. Martin S, Toquet C, Oliver L, et al. Expression of Bcl-2, Bax and bcl-xl in human gliomas: a re-appraisal. J Neurooncol, 2001, 52(2): 129-139.
11. Cartron PF, Oliver L, Martin S, et al. The expression of a new variant of the pro-apoptotic molecule Bax, Baxpsi, is correlated with an increased survival of glioblastoma multiforme patients. Hum Mol Genet, 2002, 11:675-687.
12. Bougras G, Cartron PF, Gautier F, et al. Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system. BMC Cancer, 2004, 4(1):54.
13. Kaliberov S, Stackhouse MA, Kaliberova L, et al. Enhanced apoptosis following treatment with TRA-8 anti-human DR5 monoclonal antibody and overexpression of exogenous Bax in human glioma cells. Gene Ther, 2004, 11(8):658-667.
14. Sasaki T, Lopes MB, Hankins GR, et al. Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. Acta Neuropathol (Berl), 2002, 104(1): 105-109.
15. Chakravarti A, Noll E, Black PM, et al. Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol, 2002, 20(4): 1063-1068.
16. Das A, Tan WL, Teo J, et al. Expression of survivin in primary glioblastomas. J Cancer Res Clin Oncol, 2002,128(6):302-306.
17. Chiou SK, Jones MK, Tarnawski AS. Survivin--an antiapopotosis protein: its biological roles and implications for cancer and beyond. Med Sci Monit, 2003, 9(4):125-129.
18. Uchida H, Tanaka T, Sasaki K, et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther, 2004, 10(1): 162-171.
19. Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol, 1999, 187:127-137.
20. Winter S, Weller M. Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan invovles inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. J Pharmacol Exp Ther, 1998, 286(3) :1374-1382.
21.Roth W, Wagenknecht B, Crimmel C, et al. Taxol-mediated augmentation of CD95 Ligand-induced apoptosis of human malignant glioma cells:association with Bcl-2 phosphorylation but neither a ctivation of p53 nor G2/ M cell cycle arrest. Br J Cancer, 1998, 77(3):404-411.
22. Meng RD, Phillips P. E1-Deiry-ws, P53-independent increase in E2F-2 expression enhances the cytotoxic effects of etoposide and of adriamycin. Int J Oncol, 1999,14(1):5-14.
23. Lytle RA, Jiang Z, Zheng X, et al. BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells. J Neurooncol, 2004, 68(3):233-241.
24. Zartman JK, Foreman NK, Donson AM, et al. Measurement of tamoxifen-induced apoptosis in glioblastoma by cytometric bead analysis of active caspase-3. J Neurooncol, 2004, 67(1-2):3-7.
25.Jiang Z, Zheng X, Lytle RA, et al. Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. J Neurochem, 2004, 89(1):168-178.
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