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系統識別號 U0026-0812200915312657
論文名稱(中文) 探討Gelsolin對Cisplatin抗癌藥物所產生的抗藥性所扮演的角色
論文名稱(英文) The role of Gelsolin in Cancer Drug Resistance to Cisplatin
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 97
學期 2
出版年 98
研究生(中文) 丁安安
研究生(英文) Ann-ann Ding
電子信箱 d7352102@hotmail.com
學號 t4696404
學位類別 碩士
語文別 英文
論文頁數 83頁
口試委員 指導教授-謝達斌
口試委員-陳玉玲
口試委員-劉英明
中文關鍵字 抗癌藥物抗藥性 
英文關鍵字 gelsolin  drug resistance  cisplatin 
學科別分類
中文摘要 Cisplatin已知是一種有效含鉑抗癌藥物之一,並且被廣泛的應用在治療各個部位所發生的惡性腫瘤。然而癌症病人在進行化學治療時常會衍發出抗藥性問題而導致化療失效。本研究想要了解Cisplatin抗藥性的發生原因。我們發現一種調節actin動態的蛋白質gelsolin可能跟Cisplatin抗藥性的有關,gelsolin在過去文獻中較少人去探討其與抗癌藥物抗藥性之間的關連性,但是在過去的研究中指出gelsolin是caspase-3的基質之一,能被caspase-3切割而去參與調控細胞凋亡機制,卻也同時會去反向調控caspase-3的活性來抵抗細胞凋亡。顯示出gelsolin可能具有雙面的角色去調控細胞凋亡。
因此我們觀察gelsolin與Cisplatin抗藥性的關係,在我們的研究中,利用質體轉染gelsolin到鼻咽癌細胞株HONE-1以及口腔癌細胞株SCC9中,都發現高度穩定表現gelsolin蛋白的HONE1-FullGSN和SCC9-A2以及SCC9-D2細胞株在cisplatin以及 epirubicin或5-FU抗癌藥物的施加下,其存活率會比野生型的細胞株來的高。並且經由西方墨點法分析以及JC-1染劑皆可發現高度穩定表現gelsolin蛋白會去抑制細胞內Caspase-3的活化以及粒線體膜電位的下降而降低細胞的死亡。
然而在100毫莫耳高濃度的Cisplatin藥物施加下並沒有發現gelsolin切割片斷,因此我們推測是否這些存活的HONE1-Full GSN細胞會是因為gelsolin比較不容易被切割而存活下來。因此利用質體轉染有突變在Caspase-3切割位置的gelsolin到HONE-1細胞中,發現同樣在低濃度也是會對Cisplatin產生抗藥性但在高濃度下其抗藥性卻不如有高度穩定表現gelsolin蛋白的細胞。
另外,在經由施加Cispltain所篩選出的不同抗藥程度的鼻咽癌細胞HONE1-CIS6和HONE1-CIS15細胞株,我們發現這兩株抗藥細胞株相對於HONE-1野生型細胞株gelsolin皆有較高量的表現。這樣也表示的確在這些比較抗藥的細胞可能會是經由比較高量的gelsolin蛋白而使得細胞對於Cisplatin 產生抗藥性而使得細胞比較容易存活下來。並且我們利用不同cisplatin抗藥程度的鼻咽癌細胞亦同樣觀察到,HONE1野生株和HONE1-CIS6中度抗藥的細胞株中較易出現gelsolin切割片斷,對cisplatin高度抗藥的細胞株則不會被切斷。因此由本研究發現gelsolin與cisplatin之抗藥性之關連,或許在未來可提供做為腫瘤治療抗藥性的標靶蛋白質。
英文摘要 Cisplatin is one of the most potent anti-tumor agents in clinical use for a wide variety of solid tumors. Its cytotoxic effect is mediated by attacking DNA to form intrastrand crosslink adducts. However, development of cisplatin resistance has led to clinical failures in chemotherapy. In this study, we found that overexpression of gelsolin caused multiple resistances to cisplatin, 5-FU, epirubicin and induced cell death in HONE-1 and SCC9 cell model. Gelsolin is an actin-binding/severing protein that participates in cell apoptosis and differentiation. Cleaved fragments of gelsolin have been reported to contribute DNA fragmentation and morphological alterations during apoptosis. Moreover, we discovered that cleaved gelsolin fragment has increased significantly in HONE-1 than the HONE1-Full GSN cells which is stable clone with overexpression of gelsolin. Furthermore HONE1-Full GSN cells prevented caspase-3 activation and the loss of mitochondria membrane potential with cisplatin treatment.
In high dose cisplatin treatment, the survival HONE1-Full GSN cells showed no cleavage gelsolin. Because we knew one of the targets of caspase-3 is gelsolin, thus we constructed DQTN352S in place of DQTD352G sequence of gelsolin at the caspase-3 cleavage site. The overexpression of mutant gelsolin stable clone, HONE1-Mutant GSN, was resistant to cisplatin in the low dosage treatment like HONE1-Full GSN cells, but in the high dosage it was more moderate resistant than HONE1-Full GSN cells.
In order to test our hypothesis, HONE1-CIS6 and HONE1-CIS15 cells were developed though repetitive selection of the wild type line using cisplatin containing medium. We found that gelsolin was highly expressed in cisplatin resistant HONE1-CIS6 and HONE1-CIS15 cells than the HONE-1 wild type cells. Furthermore, HONE-1and HONE1-CIS6 cells were sensitive or moderately resistant to Cisplatin than the HONE1-CIS15 resistant line. In addition, procaspase-3 also decreased and cleaved gelsolin and caspase-3 increased significantly in these lines. Further, the loss of mitochondria membrane potential reduced also could be detected in the resistant cell lines. We speculated that gelsolin may play an important role in cisplatin-induced apoptosis. For the future, we might take gelsolin to be the chemotherapeutic resistant target.
論文目次 Abstract....................................................................................................3
Chinese Abstract.......................................................................................5
Acknowledgement.................................................................................... 7
Contents.................................................................................................. 8
Figure contents ....................................................................................... 11
Table content .......................................................................................... 12
Appendix contents................................................................................... 13
1. Introduction ........................................................................................ 14
1.1. Cancer.............................................................................................. 14
1.1.1 Cancer............................................................................................ 14
1.1.2 Head and neck cancer (HNC) ......................................................... 14
1.1.3 Therapy of Cancer...........................................................................16
1.1.4 Therapy of Head and Neck Cancers (HNC) .....................................16
1.2 Chemotherapeutic drugs.....................................................................17
1.2.1 Cisplatin ........................................................................................ 17
1.2.2 Chemoresistance (Drug-resistance) ................................................. 18
1.3 Gelsolin ........................................................................................... 19
1.3.1 History and structure ..................................................................... 19
1.3.2 Function and regulation of Gelsolin in actin dynamics ..................... 20
1.3.3 Gelsolin and differentiation............................................................. 21
1.3.4 Gelsolin and Apoptosis ................................................................. 22
1.4 Gelsolin and drug resistance ............................................................. 25
1.5 Research aims................................................................................... 26
2. Materials and Methods ....................................................................... 28
2.1 Reagents .......................................................................................... 28
2.2 Cell lines and cell culture.................................................................... 29
2.3 Isolation of RNA and Quantitative Real-Time RT-PCR....................... 29
2.4 Construction for Gelsolin................................................................... 30
2.5 Transfection and establishment of stable clones ................................. 31
2.6 Protein isolation and Western blot ..................................................... 32
2.7 MTT assay....................................................................................... 34
2.8 JC-1 Staining ................................................................................... 34
3. Results .............................................................................................. 36
3.1 Overexpression of gelsolin in HONE-1 .............................................. 36
3.2 Overexpression of gelsolin caused resistance to cisplatin, 5-FU, carboplatin, epirubicin and Taxol induced cell death in HONE-1 cell model .............................................................................................................. 36
3.3 Overexpression of gelsolin prevented caspase-3 activation ................. 37
3.4 Overexpression of gelsolin prevented mitochondria membrane potential loss........................................................................................................ 38
3.5 The survival HONE1-Full GSN cells in high dose cisplatin treatment showed no cleavaged gelsolin.................................................................. 39
3.6 Overexpression of gelsolin caused resistance to cisplatin, 5-Fu and epirubicin-induced cell death in SCC9 oral squamous cell carcinoma cell 10 model .....................................................................................................40
3.7 Overexpression of mutant gelsolin in HONE-1 cells ............................40
3.8 Overexpression of mutant gelsolin in HONE-1 caused resistance to cisplatin treatment but not in HONE1-Full GSN cells ............................... 41
3.9 The cisplatin resistant cell line in HONE-1 cell model ........................ 42
3.10 Gelsolin is highly expressed in HONE1-CIS6 and HONE1-CIS15 cisplatin-resistant cells ............................................................................42
3.11 The severe cisplatin-resistant HONE1-CIS15 cells showed no cleaved gelsolin with cisplatin treatment ............................................................... 43
3.12 Expression of gelsolin, cleaved gelsolin, pro-caspase3 and caspase-3 in HONE-1, HONE1-CIS6 and HONE1-CIS15 cells ................................... 43
3.13 HONE1-CIS6 and HONE1-CIS15 cisplatin-resistant cells prevented mitochondria membrane potential loss under cisplatin treatment ...............44
4. Discussion .........................................................................................45
5. References .........................................................................................51
6. Figures ...............................................................................................62
7. Table ..................................................................................................80
8. Appendix ............................................................................................81
9. Resume ........................................ .......... .......... ............................... 83
參考文獻 1. Kiuru, S., Familial amyloidosis of the Finnish type (FAF). A clinical study of 30 patients. Acta Neurol Scand, 1992. 86(4): p. 346-53.
2. Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96.
3. Clayman GL, L.S., Laramore GE, Hong WK.,, Head and neck cancer. In: Jolland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR, eds. Cancer Medicine, 4th edn, chapter 105. Philadelphia, USA: Williams & Wilkins 1997; 1645-710.
4. Muir, C. and L. Weiland, Upper aerodigestive tract cancers. Cancer, 1995. 75(1 Suppl): p. 147-53.
5. Chen, Y.K., et al., Primary oral squamous cell carcinoma: an analysis of 703 cases in southern Taiwan. Oral Oncol, 1999. 35(2): p. 173-9.
6. Liao, C.T., et al., Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol, 2008. 15(3): p. 915-22.
7. Ko, Y.C., et al., Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med, 1995. 24(10): p. 450-3.
8. Hiltunen, T., et al., Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families. Am J Hum Genet, 1991. 49(3): p. 522-8.
9. Cobleigh, M.A., et al., Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol, 1999. 17(9): p. 2639-48.
10. Slamon, D.J., et al., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med, 2001. 344(11): p. 783-92.
11. Scarpace, S.L., et al., Treatment of head and neck cancers: issues for clinical pharmacists. Pharmacotherapy, 2009. 29(5): p. 578-92.
12. Muggia FM, R.M., Bono VH, Jacobs Jr EM. , Cisdichlorodiammineplatin II: The trail from an inert electrode to a therapeutic solution. Cancer Treat Rep, 1979. 63: p. 1431-1432.
13. Pecorelli, S., [Advanced cancer of the ovary. The paclitaxel-cisplatin combination as the first-line standard of treatment]. Recenti Prog Med, 1999. 90(6): p. 338-41.
14. Han, K., et al., First line chemotherapy with weekly docetaxel and cisplatin in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study. J Thorac Oncol, 2009. 4(4): p. 512-7.
15. Naito, Y., et al., Concurrent chemoradiotherapy with cisplatin and vinorelbine for stage III non-small cell lung cancer. J Thorac Oncol, 2008. 3(6): p. 617-22.
16. Franckena, M., et al., Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area. Int J Hyperthermia, 2007. 23(5): p. 443-50.
17. Yang, Y.C., et al., Concurrent cisplatin-based chemoradiation for cervical carcinoma: tumor response, toxicity, and serum cytokine profiles. Cancer Invest, 2006. 24(4): p. 390-5.
18. Lee, K.C., et al., Prospective pilot study of consolidation chemotherapy with docetaxel and cisplatin after concurrent chemoradiotherapy for advanced head and neck cancer. Int J Radiat Oncol Biol Phys, 2008. 71(1): p. 187-91.
19. Guntinas-Lichius, O., et al., Quality of life during first-line palliative chemotherapy for recurrent and metastatic head and neck cancer with weekly cisplatin and docetaxel. J Cancer Res Clin Oncol, 2008.
20. Eastman, A., The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther, 1987. 34(2): p. 155-66.
21. Pinto, A.L. and S.J. Lippard, Binding of the antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) to DNA. Biochim Biophys Acta, 1985. 780(3): p. 167-80.
22. Ozols, R.F., Ovarian cancer: new clinical approaches. Cancer Treat Rev, 1991. 18 Suppl A: p. 77-83.
23. Boven, E., et al., New analogues of camptothecins. Activity and resistance. Ann N Y Acad Sci, 2000. 922: p. 175-7.
24. Ozols, R.F., Chemotherapy for advanced epithelial ovarian cancer. Hematol Oncol Clin North Am, 1992. 6(4): p. 879-94.
25. Yin, H.L. and T.P. Stossel, Control of cytoplasmic actin gel-sol transformation by gelsolin, a calcium-dependent regulatory protein. Nature, 1979. 281(5732): p. 583-6.
26. Sun, H.Q., et al., Gelsolin, a multifunctional actin regulatory protein. J Biol Chem, 1999. 274(47): p. 33179-82.
27. Yin, H.L., et al., Structure and biosynthesis of cytoplasmic and secreted variants of gelsolin. J Biol Chem, 1984. 259(8): p. 5271-6.
28. Rithidech, K., et al., Protein expression profiles in pediatric multiple sclerosis: potential biomarkers. Mult Scler, 2009. 15(4): p. 455-64.
29. Wiederin, J., et al., Biomarkers of HIV-1 associated dementia: proteomic investigation of sera. Proteome Sci, 2009. 7: p. 8.
30. Vouyiouklis, D.A. and P.J. Brophy, A novel gelsolin isoform expressed by oligodendrocytes in the central nervous system. J Neurochem, 1997. 69(3): p. 995-1005.
31. Kiselar, J.G., et al., Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting. Proc Natl Acad Sci U S A, 2003. 100(7): p. 3942-7.
32. McLaughlin, P.J., et al., Structure of gelsolin segment 1-actin complex and the mechanism of filament severing. Nature, 1993. 364(6439): p. 685-92.
33. Choe, H., et al., The calcium activation of gelsolin: insights from the 3A structure of the G4-G6/actin complex. J Mol Biol, 2002. 324(4): p. 691-702.
34. Liepina, I., et al., Molecular dynamics study of a gelsolin-derived peptide binding to a lipid bilayer containing phosphatidylinositol 4,5-bisphosphate. Biopolymers, 2003. 71(1): p. 49-70.
35. Yu, F.X., et al., Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J Biol Chem, 1992. 267(21): p. 14616-21.
36. Kazmirski, S.L., et al., Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type. Nat Struct Biol, 2002. 9(2): p. 112-6.
37. Silacci, P., et al., Gelsolin superfamily proteins: key regulators of cellular functions. Cell Mol Life Sci, 2004. 61(19-20): p. 2614-23.
38. Lee, W.M. and R.M. Galbraith, The extracellular actin-scavenger system and actin toxicity. N Engl J Med, 1992. 326(20): p. 1335-41.
39. Witke, W., et al., Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin. Cell, 1995. 81(1): p. 41-51.
40. Azuma, T., et al., Gelsolin is a downstream effector of rac for fibroblast motility. EMBO J, 1998. 17(5): p. 1362-70.
41. Lu, M., et al., Delayed retraction of filopodia in gelsolin null mice. J Cell Biol, 1997. 138(6): p. 1279-87.
42. Cunningham, C.C., T.P. Stossel, and D.J. Kwiatkowski, Enhanced motility in NIH 3T3 fibroblasts that overexpress gelsolin. Science, 1991. 251(4998): p. 1233-6.
43. De Corte, V., et al., Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling. EMBO J, 2002. 21(24): p. 6781-90.
44. Noske, A., et al., Loss of Gelsolin expression in human ovarian carcinomas. Eur J Cancer, 2005. 41(3): p. 461-9.
45. Rao, J., et al., Tissue microarray analysis of cytoskeletal actin-associated biomarkers gelsolin and E-cadherin in urothelial carcinoma. Cancer, 2002. 95(6): p. 1247-57.
46. Dong, Y., et al., Concurrent deregulation of gelsolin and cyclin D1 in the majority of human and rodent breast cancers. Int J Cancer, 1999. 81(6): p. 930-8.
47. Winston, J.S., et al., Downregulation of gelsolin correlates with the progression to breast carcinoma. Breast Cancer Res Treat, 2001. 65(1): p. 11-21.
48. Dosaka-Akita, H., et al., Frequent loss of gelsolin expression in non-small cell lung cancers of heavy smokers. Cancer Res, 1998. 58(2): p. 322-7.
49. Lee, H.K., et al., Downregulated gelsolin expression in hyperplastic and neoplastic lesions of the prostate. Prostate, 1999. 40(1): p. 14-9.
50. Visapaa, H., et al., Correlation of Ki-67 and gelsolin expression to clinical outcome in renal clear cell carcinoma. Urology, 2003. 61(4): p. 845-50.
51. Kim, J.H., et al., Downregulation of gelsolin and retinoic acid receptor beta expression in gastric cancer tissues through histone deacetylase 1. J Gastroenterol Hepatol, 2004. 19(2): p. 218-24.
52. Tanaka, M., et al., Gelsolin: a candidate for suppressor of human bladder cancer. Cancer Res, 1995. 55(15): p. 3228-32.
53. Fujita, H., et al., Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect. Int J Cancer, 2001. 93(6): p. 773-80.
54. Kwiatkowski, D.J., et al., Localization of gelsolin proximal to ABL on chromosome 9. Am J Hum Genet, 1988. 42(4): p. 565-72.
55. Paunio, T., et al., Tissue distribution and levels of gelsolin mRNA in normal individuals and patients with gelsolin-related amyloidosis. FEBS Lett, 1997. 406(1-2): p. 49-55.
56. Tanaka, J. and K. Sobue, Localization and characterization of gelsolin in nervous tissues: gelsolin is specifically enriched in myelin-forming cells. J Neurosci, 1994. 14(3 Pt 1): p. 1038-52.
57. Maury, P., [Finnish hereditary amyloidosis: a mutation in the gelsolin gene]. Duodecim, 1994. 110(7): p. 675-80.
58. Maury, C.P., K. Alli, and M. Baumann, Finnish hereditary amyloidosis. Amino acid sequence homology between the amyloid fibril protein and human plasma gelsoline. FEBS Lett, 1990. 260(1): p. 85-7.
59. Maury, C.P., et al., Homozygosity for the Asn187 gelsolin mutation in Finnish-type familial amyloidosis is associated with severe renal disease. Genomics, 1992. 13(3): p. 902-3.
60. Weeds, A.G., et al., Variant plasma gelsolin responsible for familial amyloidosis (Finnish type) has defective actin severing activity. FEBS Lett, 1993. 335(1): p. 119-23.
61. Westberg, J.A., K.Z. Zhang, and L.C. Andersson, Regulation of neural differentiation by normal and mutant (G654A, amyloidogenic) gelsolin. FASEB J, 1999. 13(12): p. 1621-6.
62. Philchenkov, A.A., Caspases as regulators of apoptosis and other cell functions. Biochemistry (Mosc), 2003. 68(4): p. 365-76.
63. Green, D. and G. Kroemer, The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol, 1998. 8(7): p. 267-71.
64. Kothakota, S., et al., Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science, 1997. 278(5336): p. 294-8.
65. Kamada, S., et al., A cloning method for caspase substrates that uses the yeast two-hybrid system: cloning of the antiapoptotic gene gelsolin. Proc Natl Acad Sci U S A, 1998. 95(15): p. 8532-7.
66. Azuma, T., et al., Gelsolin in complex with phosphatidylinositol 4,5-bisphosphate inhibits caspase-3 and -9 to retard apoptotic progression. J Biol Chem, 2000. 275(6): p. 3761-6.
67. Ohtsu, M., et al., Inhibition of apoptosis by the actin-regulatory protein gelsolin. EMBO J, 1997. 16(15): p. 4650-6.
68. Petit, P.X., et al., Implication of mitochondria in apoptosis. Mol Cell Biochem, 1997. 174(1-2): p. 185-8.
69. Saleh, A., et al., Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J Biol Chem, 1999. 274(25): p. 17941-5.
70. Koya, R.C., et al., Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release. J Biol Chem, 2000. 275(20): p. 15343-9.
71. Ahn, J.S., et al., Aging-associated increase of gelsolin for apoptosis resistance. Biochem Biophys Res Commun, 2003. 312(4): p. 1335-41.
72. Ahn, J.S., et al., Gelsolin for senescence-associated resistance to apoptosis. Ann N Y Acad Sci, 2003. 1010: p. 493-5.
73. Mejillano, M., et al., Regulation of apoptosis by phosphatidylinositol 4,5-bisphosphate inhibition of caspases, and caspase inactivation of phosphatidylinositol phosphate 5-kinases. J Biol Chem, 2001. 276(3): p. 1865-72.
74. Endres, M., et al., Neuroprotective effects of gelsolin during murine stroke. J Clin Invest, 1999. 103(3): p. 347-54.
75. Li, G.H., et al., Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. Circ Res, 2009. 104(7): p. 896-904.
76. Ji, L., A. Chauhan, and V. Chauhan, Cytoplasmic gelsolin in pheochromocytoma-12 cells forms a complex with amyloid beta-protein. Neuroreport, 2008. 19(4): p. 463-6.
77. Keller, J.W., et al., Oncogenic K-RAS subverts the antiapoptotic role of N-RAS and alters modulation of the N-RAS:gelsolin complex. Oncogene, 2007. 26(21): p. 3051-9.
78. Sakurai, N. and T. Utsumi, Posttranslational N-myristoylation is required for the anti-apoptotic activity of human tGelsolin, the C-terminal caspase cleavage product of human gelsolin. J Biol Chem, 2006. 281(20): p. 14288-95.
79. Li, Q., et al., Gelsolin, but not its cleavage, is required for TNF-induced ROS generation and apoptosis in MCF-7 cells. Biochem Biophys Res Commun, 2009. 385(2): p. 284-9.
80. Klampfer, L., et al., Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression. J Biol Chem, 2004. 279(35): p. 36680-8.
81. Klampfer, L., et al., Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis. Oncogene, 2005. 24(24): p. 3932-41.
82. Siddik, Z.H., Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene, 2003. 22(47): p. 7265-79.
83. Achanzar, W.E., M.M. Webber, and M.P. Waalkes, Altered apoptotic gene expression and acquired apoptotic resistance in cadmium-transformed human prostate epithelial cells. Prostate, 2002. 52(3): p. 236-44.
84. Isonishi, S., et al., Mitochondria in platinum resistant cells. Hum Cell, 2001. 14(3): p. 203-10.
85. Control of oral cancer in developing countries. A WHO meeting. Bull World Health Organ, 1984. 62(6): p. 817-30.
86. Gottesman, M.M., et al., Defeating drug resistance in cancer. Discov Med, 2006. 6(31): p. 18-23.
87. Gottesman, M.M., T. Fojo, and S.E. Bates, Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer, 2002. 2(1): p. 48-58.
88. Geng, Y.J., et al., Caspase-3-induced gelsolin fragmentation contributes to actin cytoskeletal collapse, nucleolysis, and apoptosis of vascular smooth muscle cells exposed to proinflammatory cytokines. Eur J Cell Biol, 1998. 77(4): p. 294-302.
89. Qiao, H., et al., Inhibition of Alzheimer's amyloid-beta peptide-induced reduction of mitochondrial membrane potential and neurotoxicity by gelsolin. Neurobiol Aging, 2005. 26(6): p. 849-55.
90. Chen-Levy, Z., J. Nourse, and M.L. Cleary, The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol Cell Biol, 1989. 9(2): p. 701-10.
91. Franke, T.F., D.R. Kaplan, and L.C. Cantley, PI3K: downstream AKTion blocks apoptosis. Cell, 1997. 88(4): p. 435-7.
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