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系統識別號 U0026-2207201615405500
論文名稱(中文) 探討白藜蘆醇在人類乳癌細胞株中的效果及其分子作用機轉
論文名稱(英文) Evaluating the potency and investigating the molecular mechanism of actions of Resveratrol in human breast cancer cells
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 104
學期 2
出版年 105
研究生(中文) 林宭卉
研究生(英文) Chun-Hui Lin
學號 S26034112
學位類別 碩士
語文別 英文
論文頁數 72頁
口試委員 指導教授-張雋曦
口試委員-張俊彥
口試委員-呂增宏
口試委員-陳韻雯
中文關鍵字 乳癌  白藜蘆醇  存活素  Bcl-2  組蛋白去乙醯酶 
英文關鍵字 Breast cancer  resveratrol  survivin  Bcl-2  HDAC 
學科別分類
中文摘要 乳癌是目前排名第三且好發於女性的癌症。此外,在臨床中,對於陽性雌激素受體、具他莫西芬抗藥性之乳癌以及三陰性乳癌仍有治療上的瓶頸。白藜蘆醇是在葡萄及紅葡萄酒中一個天然的抗氧化物,有趣的是,許多研究指出白藜蘆醇具有廣泛的藥理特性並且具有作為抗癌藥物的潛力。然而,儘管白藜蘆醇抗癌的效果已被廣泛的研究,但其確切的分子作用機制仍然不明。此外,白藜蘆醇對於不同亞型的乳癌患者是否可作為治療藥物目前也未知。

在本研究中,我們發現儘管白藜蘆醇對於管腔A型的MCF7、MCF7衍生出之陽性雌激素受體-抗他莫西芬之MCF7-TamC3、HER2表現型的SK-BR-3以及三陰性的MDA-MB-231乳癌細胞都會抑制細胞的存活。但在體內實驗中發現,白藜蘆醇在不同的乳癌細胞中具有不同的抗增生能力以及不同程度的毒殺能力。從顯微鏡觀察、Brdu細胞生長速率測試、及LDH細胞毒性測試的分析中顯示,用MTT 細胞存活測試得到的兩倍IC50濃度的白藜蘆醇在MCF7及SK-BR-3乳癌細胞中會誘導早期的細胞增生抑制(給藥後24小時)以及細胞死亡(給藥後48小時)。意外的是,兩倍IC50濃度的白藜蘆醇在MDA-MB-231乳癌細胞中則會延緩細胞增生抑制以及細胞死亡。在分子層次,西方墨點法分析指出在MCF7以及SK-BR-3乳癌細胞中,白藜蘆醇會在給藥24小時後增加DNA損傷的標誌- γH2AX的蛋白表現。相反的,在MDA-MB-231乳癌細胞中則是在給藥後48小時後才觀察到γH2AX的蛋白表現有增加的情形。值得注意的是,使用Brdu細胞生長速率測試取代MTT細胞存活測試,重新分析白藜蘆醇在不同細胞中的IC50濃度,結果顯示在MDA-MB-231乳癌細胞中,其測得的IC50濃度比MCF7以及SK-BR-3乳癌細胞測得的濃度高出了至少2倍。這些結果顯示了MDA-MB-231乳癌細胞在體內實驗中比MCF7以及SK-BR-3乳癌細胞更具抗藥性。在分子機制研究中顯示,白藜蘆醇在MCF7, SK-BR-3以及MDA-MB-231乳癌細胞中都會抑制屬於抑制凋亡蛋白家族成員中的IAP-2之蛋白表現,意外的是,白藜蘆醇只會在MCF7以及SK-BR-3乳癌細胞中抑制同屬於抑制凋亡蛋白家族成員中的存活素蛋白表現。事實上,白藜蘆醇在MDA-MB-231乳癌細胞中增加了存活素蛋白的表現以及提高存活素蛋白的穩定性。除此之外,白藜蘆醇在這三種測試的乳癌細胞株中都增加了Bcl-2這個已知的抑制細胞凋亡的蛋白之表現。

綜合上述結果,我們的發現顯示白藜蘆醇在不同的乳癌細胞中有不同的作用效果,而此結果可能是透過存活素不同的調控造成。此外,透過和標靶Bcl-2的合併治療可能可以對白藜蘆醇在臨床應用上所遇到的困難提供一個較佳的選擇,此篇研究結果對於未來在使用白藜蘆醇作為治療藥物時,針對特定的乳癌患者能提供重要的資訊。
英文摘要 Breast cancer ranks the top three cancers with high incidence rate among women. In addition, treating patients with estrogen receptor positive tamoxifen-resistant breast cancer and triple-negative breast cancer remains to be a therapeutic challenge in clinical situations. Resveratrol (3, 5, 4'- trans- trihydroxystilbene) is an anti-oxidant found in grapes and red wine. Interestingly, resveratrol has been shown to exhibit a wide spectrum of pharmacological properties with potential to be an anti-cancer agent. However, despite the anti-cancer effect of resveratrol has already been shown in a few studies, its molecular mechanism of actions are still incompletely known. Furthermore, it is still unclear on whether resveratrol can be used as a therapeutic agent for patients with different breast cancer subtypes.

In this study, we found that despite resveratrol exhibits similar cell viability inhibitory effects on the lumen A-like MCF7, MCF7-derivded tamoxifen-resistant MCF7-TamC3, HER2-like SK-BR-3, and basal-like triple-negative MDA-MB-231 breast cancer cells, it exhibits differential anti-proliferative effects and cytotoxicity towards different breast cancer cells in vitro. Results of the microscopic analysis, Brdu cell proliferation assay and LDH cytotoxicity assay showed that 2xIC50(MTT) (as determined by the MTT assay) resveratrol induced early cell proliferation inhibition (24 h post-treatment) and cell death (48 h post-treatment) in MCF7 and SK-BR-3 cells. Surprisingly, 2xIC50(MTT) resveratrol induced delayed cell proliferation inhibition and cell death in MDA-MB-231 cells. At the molecular level, Western blot analysis revealed that resveratrol increased the expression of gamma H2AX, which is a DNA damage marker, in MCF7 and SK-BR-3 as early as 24 h post-treatment. In contrast, increased expression of gamma H2AX was only observed in MDA-MB-231 cells 48 h post-treatment. Noticeably, re-determination of the IC50 values using the Brdu cell proliferation assay [IC50(Brdu)] instead of the originally used MTT cell viability assay showed that the IC50(Brdu) of resveratrol in MDA-MB-231 cells is at least 2-fold higher than that in MCF7 and SK-BR-3 cells. These results indicate that MDA-MB-231 cells are more resistant to resveratrol than MCF7 and SK-BR-3 cells in vitro. Mechanistic studies revealed that resveratrol decreased the expression of IAP-2, which is a member of the inhibitor-of-apoptosis proteins (IAPs) family, in MCF7, SK-BR-3 and MDA-MB-231 cells. Surprisingly, resveratrol only decreased the expression of survivin in MCF7 and SK-BR-3 cells but not in MDA-MB-231 cells. Indeed, resveratrol increased the expression of survivin and increased the stability of survivin protein in MDA-MB-231 cells. Moreover, resveratrol also up-regulated the expression of Bcl-2, which is a well-known inhibitor of apoptosis, in all of the tested breast cancer cell lines.

Taken together, our findings indicate that resveratrol induced differential cellular effects at least in part through differential regulation of survivin expression in different breast cancer subtypes. In addition, combination of Bcl-2 targeted therapy may provide a better therapeutic option against the odds of resveratrol in clinical application. Results of this study may provide important information for the use of resveratrol as a therapeutic agent for specific breast cancer subpopulations in the future.
論文目次 中文摘要............................................... II
ABSTRACT............................................... V
誌謝................................................ VIII
Abbreviation.......................................... IX
List of Tables....................................... XII
List of Figures..................................... XIII
List of Appendices.................................... XV
INTRODUCTION........................................... 1
1.1. Breast Cancer..................................... 2
1.1.1. The epidemiology of breast cancer............... 2
1.1.2. Treatments of breast cancer..................... 2
1.1.3. Challenges in breast cancer treatment........... 4
1.2. Resveratrol (3, 5, 4'-trans-trihydroxystilbene)... 4
1.2.1. Biological effects of Resveratrol............... 4
1.2.2. Resveratrol and cancer.......................... 5
1.3. Inhibitor of Apoptosis Proteins (IAPs)................................................. 6
1.3.1. IAP family and cancer........................... 6
1.3.2. Survivin and cancer............................. 7
1.3.3. Functions of survivin........................... 8
1.3.4. Regulation of survivin in cancer................ 9
1.4. Aims of this study............................... 11
MATERIALS AND METHODS................................. 12
2.1. Materials........................................ 13
2.2. Recipes.......................................... 16
2.3. Methods.......................................... 18
2.3.1. Cells and culture.............................. 18
2.3.2. MTT cell viability assay....................... 19
2.3.3. Bromodeoxyuridine (BrdU) cell proliferation assay .......................................................19
2.3.4. Lactate dehydrogenase (LDH) cell cytotoxicity assay ................................................ 20
2.3.5. Comet assay.................................... 20
2.3.6. Western blot analysis.......................... 21
2.3.7. Gene silencing by siRNA........................ 22
2.3.8. Protein stability Assay........................ 22
2.3.9. Gene Set Analysis-Tumor settings............... 23
2.3.10. Statistic analysis............................ 23
RESULTS............................................... 24
3.1. Resveratrol induces differential cellular effects in different breast cancer subtypes.......................25
3.2. Resveratrol induces differential anti-proliferative effects and DNA damages in MCF7, SK-BR-3 and MDA-MB-231 cells................................................. 26
3.3. Resveratrol induces differential molecular effects in MCF7, SK-BR-3 and MDA-MB-231 cells................. 27
3.4. Differential regulation of survivin expression plays an important role in the differential potency of resveratrol exhibited in different breast cancer cells.28
3.5. Resveratrol increases the expression of survivin through mTOR-4E-BP1- and protein stability- independent pathway in MDA-MB-231 cells .................. ........30
3.6. Resveratrol down-regulates the expression of HDAC2 in breast cancer cells................................ 30
DISCUSSION &.......................................... 32
CONCLUSIONS........................................... 32
4.1. Discussion....................................... 33
4.2. Conclusions...................................... 36
REFERENCES............................................ 37
TABLES................................................ 50
FIGURES............................................... 55
APPENDICES............................................ 69
參考文獻 Agarwal, A., & Prabakaran, S. A. (2005). Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian J Exp Biol, 43(11), 963-974.
Aluyen, J. K., Ton, Q. N., Tran, T., Yang, A. E., Gottlieb, H. B., & Bellanger, R. A. (2012). Resveratrol: potential as anticancer agent. J Diet Suppl, 9(1), 45-56.
Aziz, M. H., Nihal, M., Fu, V. X., Jarrard, D. F., & Ahmad, N. (2006). Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3′-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther, 5(5), 1335-1341.
Bendell, J. C., Domchek, S. M., Burstein, H. J., Harris, L., Younger, J., Kuter, I. et al. (2003). Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer, 97(12), 2972-2977.
Boocock, D. J., Faust, G. E., Patel, K. R., Schinas, A. M., Brown, V. A., Ducharme, M. P. et al. (2007). Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev, 16(6), 1246-1252.
Campos, L., Rouault, J. P., Sabido, O., Oriol, P., Roubi, N., Vasselon, C. et al. (1993). High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood, 81(11), 3091-3096.
Cang, S., Iragavarapu, C., Savooji, J., Song, Y., & Liu, D. (2015). ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol, 8, 129.
Cao, Y., Fu, Z.-D., Wang, F., Liu, H.-Y., & Han, R. (2005). Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants. J Asian Nat Prod Res, 7(3), 205-213.
Cao, Z., Fang, J., Xia, C., Shi, X., & Jiang, B.-H. (2004). trans-3,4,5′-Trihydroxystibene Inhibits Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells. Clin Cancer Res, 10(15), 5253-5263.
Carter, Z. B., & Andreeff, M. (2015). IAP Family of Proteins as Therapeutic Targets for Acute Myeloid Leukemia. In M. Andreeff (Ed.), Targeted Therapy of Acute Myeloid Leukemia (pp. 95-121). New York, NY: Springer New York.
Chang, M. (2012). Tamoxifen Resistance in Breast Cancer. Biomol Ther (Seoul), 20(3), 256-267.
Chang, Y.-J., Li, L.-T., Chen, H.-A., Hung, C.-S., & Wei, P.-L. (2014). Silencing survivin activates autophagy as an alternative survival pathway in HCC cells. Tumour Biol, 35(10), 9957-9966.
Chen, P., Zhu, J., Liu, D.-y., Li, H.-y., Xu, N., & Hou, M. (2013). Over-expression of survivin and VEGF in small-cell lung cancer may predict the poorer prognosis. Med Oncol, 31(1), 1-7.
Chen, X., Wang, T., Yang, D., Wang, J., Li, X., He, Z. et al. (2013). Expression of the IAP protein family acts cooperatively to predict prognosis in human bladder cancer patients. Oncol Lett, 5(4), 1278-1284.
Cheng, S. M., Chang, Y. C., Liu, C. Y., Lee, J. Y. C., Chan, H. H., Kuo, C. W. et al. (2015). YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. Br J Pharmacol, 172(1), 214-234.
Cheung, C. H., Huang, C. C., Tsai, F. Y., Lee, J. Y., Cheng, S. M., Chang, Y. C. et al. (2013). Survivin - biology and potential as a therapeutic target in oncology. Onco Targets Ther, 6, 1453-1462.
Chu, X. Y., Chen, L. B., Wang, J. H., Su, Q. S., Yang, J. R., Lin, Y. et al. (2012). Overexpression of survivin is correlated with increased invasion and metastasis of colorectal cancer. J Surg Oncol, 105(6), 520-528.
Daugas, E., Susin, S. A., Zamzami, N., Ferri, K. F., Irinopoulou, T., Larochette, N. et al. (2000). Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J, 14(5), 729-739.
Dhar, S., Kumar, A., Li, K., Tzivion, G., & Levenson, A. S. (2015). Resveratrol regulates PTEN/Akt pathway through inhibition of MTA1/HDAC unit of the NuRD complex in prostate cancer. Biochim Biophys Acta , 1853(2), 265-275.
Dohi, T., Okada, K., Xia, F., Wilford, C. E., Samuel, T., Welsh, K. et al. (2004). An IAP-IAP complex inhibits apoptosis. J Biol Chem, 279(33), 34087-34090.
Dong H, Yao L, Bi W, Wang F, Song W, & Y., L. (2015). Combination of survivin siRNA with neoadjuvant chemotherapy enhances apoptosis and reverses drug resistance in breast cancer MCF-7 cells. J Can Res Ther, (11), 717-722.
Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42.
Early Breast Cancer Trialists' Collaborative, G. (2015). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet, 386(10001), 1341-1352.
Ellis, L., Atadja, P. W., & Johnstone, R. W. (2009). Epigenetics in cancer: Targeting chromatin modifications. Mol Cancer Ther, 8(6), 1409-1420.
Fang, Y., Bradley, M. J., Cook, K. M., Herrick, E. J., & Nicholl, M. B. (2013). A potential role for resveratrol as a radiation sensitizer for melanoma treatment. J Surg Res, 183(2), 645-653.
Faversani, A., Vaira, V., Moro, G. P., Tosi, D., Lopergolo, A., Schultz, D. C. et al. (2014). Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors. Breast Cancer Res, 16(3), 1-13.
Fernández, J. G., Rodríguez, D. A., Valenzuela, M., Calderon, C., Urzúa, U., Munroe, D. et al. (2014). Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription. Mol Cancer, 13(1), 1-15.
Foulkes , W. D., Smith , I. E., & Reis-Filho , J. S. (2010). Triple-Negative Breast Cancer. N Engl J Med, 363(20), 1938-1948.
Fremont, L. (2000). Biological effects of resveratrol. Life Sci, 66(8), 663-673.
Fulda, S. (2010). Resveratrol and derivatives for the prevention and treatment of cancer. Drug Discov Today, 15(17–18), 757-765.
Gülçin, İ. (2010). Antioxidant properties of resveratrol: A structure–activity insight. Innov Food Sci Emerg Technol, 11(1), 210-218.
Gillard, M., Upham, K., Pogozelski, W., & O'Donnell, R. (2015). Resveratrol and Radiation: Cytotoxicity and Cell Cycle Analysis. FASEB J, 29(1 Supplement).
Gu, X., & Lin, H.-L. (2004). [Analysis of survivin expression in subtypes of lymphoma]. Ai Zheng, 23(6), 655-661.
Hausenblas, H. A., Schoulda, J. A., & Smoliga, J. M. (2015). Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Mol Nutr Food Res, 59(1), 147-159.
Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J., & Murphy, M. (2002). Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem, 277(5), 3247-3257.
Isakoff, S. J. (2010). Triple Negative Breast Cancer: Role of Specific Chemotherapy Agents. Cancer J, 16(1), 53-61.
Jazirehi, A. R., & Bonavida, B. (2004). Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol Cancer Ther, 3(1), 71-84.
Johnston, S. R. D., Saccani-Jotti, G., Smith, I. E., Salter, J., Newby, J., Coppen, M. et al. (1995). Changes in Estrogen Receptor, Progesterone Receptor, and pS2 Expression in Tamoxifen-resistant Human Breast Cancer. Cancer Res, 55(15), 3331-3338.
Kumar, A., Naidu, P. S., Seghal, N., & Padi, S. S. (2007). Neuroprotective effects of resveratrol against intracerebroventricular colchicine- induced cognitive impairment and oxidative stress in rats. Pharmacology, 79(1), 17-26.
Lee, J. Y.-C., Kuo, C.-W., Tsai, S.-L., Cheng, S. M., Chen, S.-H., Chan, H.-H. et al.. (2016). Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells. Front Pharmacol, 7, 81.
Leung, E., Kannan, N., Krissansen, G. W., Findlay, M. P., & Baguley, B. C. (2010). MCF-7 breast cancer cells selected for tamoxifen resistance acquire new phenotypes differing in DNA content, phospho-HER2 and PAX2 expression, and rapamycin sensitivity. Cancer Biol Ther, 9(9), 717-724.
Liu, S., Huang, W., Jin, M.-J., Fan, B., Xia, G.-M., & Gao, Z.-G. (2016). Inhibition of murine breast cancer growth and metastasis by survivin-targeted siRNA using disulfide cross-linked linear PEI. Eur J Pharm Sci, 82, 171-182.
Liu, T., Brouha, B., & Grossman, D. (2004). Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells. Oncogene, 23(1), 39-48.
Liu, Z., Sun, C., Olejniczak, E. T., Meadows, R. P., Betz, S. F., Oost, T. et al. (2000). Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature, 408(6815), 1004-1008.
Lopes, R. B., Gangeswaran, R., McNeish, I. A., Wang, Y., & Lemoine, N. R. (2007). Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer, 120(11), 2344-2352.
Marambaud, P., Zhao, H., & Davies, P. (2005). Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem, 280(45), 37377-37382.
McKenzie, J. A., Liu, T., Jung, J. Y., Jones, B. B., Ekiz, H. A., Welm, A. L. et al. (2013). Survivin promotion of melanoma metastasis requires upregulation of alpha5 integrin. Carcinogenesis, 34(9), 2137-2144.
Miki, H., Uehara, N., Kimura, A., Sasaki, T., Yuri, T., Yoshizawa, K. et al. (2012). Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol, 40(4), 1020-1028.
Mirza, A., McGuirk, M., Hockenberry, T. N., Wu, Q., Ashar, H., Black, S. et al. (2002). Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 21(17), 2613-2622.
Mita, A. C., Mita, M. M., Nawrocki, S. T., & Giles, F. J. (2008). Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics. Clin Cancer Res, 14(16), 5000-5005.
Mobahat, M., Narendran, A., & Riabowol, K. (2014). Survivin as a preferential target for cancer therapy. Int J Mol Sci, 15(2), 2494-2516.
Moriai, R., Tsuji, N., Moriai, M., Kobayashi, D., & Watanabe, N. (2009). Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat, 117(2), 261-271.
Morrison, D. J., Hogan, L. E., Condos, G., Bhatla, T., Germino, N., Moskowitz, N. P. et al. (2012). Endogenous knockdown of survivin improves chemotherapeutic response in ALL models. Leukemia, 26(2), 271-279.
Nomura, T., Yamasaki, M., Nomura, Y., & Mimata, H. (2005). Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. Oncol Rep, 14(4), 993-997.
O'Connor, D. J., Lam, E. W., Griffin, S., Zhong, S., Leighton, L. C., Burbidge, S. A. et al. (1995). Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1. EMBO J, 14(24), 6184-6192.
Opipari, A. W., Tan, L., Boitano, A. E., Sorenson, D. R., Aurora, A., & Liu, J. R. (2004). Resveratrol-induced Autophagocytosis in Ovarian Cancer Cells. Cancer Res, 64(2), 696-703.
Ozbay, T., Durden, D. L., Liu, T., O'Regan, R. M., & Nahta, R. (2010). In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells. Cancer Chemother Pharmacol, 65(4), 697-706.
Pangeni, R., Sahni, J. K., Ali, J., Sharma, S., & Baboota, S. (2014). Resveratrol: review on therapeutic potential and recent advances in drug delivery. Expert Opinion Drug Deliv, 11(8), 1285-1298.
Ribe, Elena M., Serrano-Saiz, E., Akpan, N., & Troy, Carol M. (2008). Mechanisms of neuronal death in disease: defining the models and the players. Biochem J, 415(2), 165-182.
Richard, J. L., Cambien, F., & Ducimetiere, P. (1981). [Epidemiologic characteristics of coronary disease in France]. Nouv Presse Med, 10(14), 1111-1114.
Ringnér, M., Fredlund, E., Häkkinen, J., Borg, Å., & Staaf, J. (2011). GOBO: Gene Expression-Based Outcome for Breast Cancer Online. PLoS ONE, 6(3), e17911.
Roca, H., Varsos, Z., & Pienta, K. J. (2008). CCL2 Protects Prostate Cancer PC3 Cells from Autophagic Death via Phosphatidylinositol 3-Kinase/AKT- dependent Survivin Up-regulation. J Biol Chem, 283(36), 25057-25073.
Sarela, A. I., Macadam, R. C., Farmery, S. M., Markham, A. F., & Guillou, P. J. (2000). Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut, 46(5), 645-650.
Shariat, S. F., Lotan, Y., Saboorian, H., Khoddami, S. M., Roehrborn, C. G., Slawin, K. M. et al. (2004). Survivin expression is associated with features of biologically aggressive prostate carcinoma. Cancer, 100(4), 751-757.
Shin, S., Sung, B.-J., Cho, Y.-S., Kim, H.-J., Ha, N.-C., Hwang, J.-I. et al. (2001). An Anti-apoptotic Protein Human Survivin Is a Direct Inhibitor of Caspase-3 and -7. Biochemistry, 40(4), 1117-1123.
Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J Clin, 66(1), 7-30.
Silke, J., & Vucic, D. (2014). Chapter Two - IAP Family of Cell Death and Signaling Regulators. In J. A. W. Avi Ashkenazi & Y. Junying (Eds.), Methods in Enzymology (Vol. 545, pp. 35-65): Academic Press.
Song, Z., Yao, X., & Wu, M. (2003). Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem, 278(25), 23130-23140.
Speit, G., & Rothfuss, A. (2012). The comet assay: a sensitive genotoxicity test for the detection of DNA damage and repair. Methods Mol Biol, 920, 79-90.
Sun, X. P., Dong, X., Lin, L., Jiang, X., Wei, Z., Zhai, B. et al. (2014). Up-regulation of survivin by AKT and hypoxia-inducible factor 1alpha contributes to cisplatin resistance in gastric cancer. FEBS J, 281(1), 115-128.
Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M. et al. (1999). Molecular characterization of mitochondrial apoptosis-inducing factor. Nature, 397(6718), 441-446.
Szkudelski, T., & Szkudelska, K. (2011). Anti-diabetic effects of resveratrol. Ann N Y Acad Sci, 1215, 34-39.
Tirrò, E., Consoli, M. L., Massimino, M., Manzella, L., Frasca, F., Sciacca, L. et al. (2006). Altered Expression of c-IAP1, Survivin, and Smac Contributes to Chemotherapy Resistance in Thyroid Cancer Cells. Cancer Res, 66(8), 4263-4272.
Tome-Carneiro, J., Larrosa, M., Gonzalez-Sarrias, A., A. Tomas-Barberan, F., Teresa Garcia-Conesa, M., & Carlos Espin, J. (2013). Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence. Curr Pharm Des, 19(34), 6064-6093.
Tsai, H.-C., Huang, C.-Y., Su, H.-L., & Tang, C.-H. (2014). CTGF increases drug resistance to paclitaxel by upregulating survivin expression in human osteosarcoma cells. Biochim Biophys Acta, 1843(5), 846-854.
Tsubaki, M., Takeda, T., Ogawa, N., Sakamoto, K., Shimaoka, H., Fujita, A. et al. (2015). Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells. Leuk Res, 39(4), 445-452.
Umar, A., Kang, H., Timmermans, A. M., Look, M. P., Meijer-van Gelder, M. E., den Bakker, M. A. et al. (2009). Identification of a putative protein profile associated with tamoxifen therapy resistance in breast cancer. Mol Cell Proteomics, 8(6), 1278-1294.
Vader, G., Kauw, J. J. W., Medema, R. H., & Lens, S. M. A. (2006). Survivin mediates targeting of the chromosomal passenger complex to the centromere and midbody. EMBO Rep, 7(1), 85-92.
Vaira, V., Lee, C. W., Goel, H. L., Bosari, S., Languino, L. R., & Altieri, D. C. (2007). Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene, 26(19), 2678-2684.
Velculescu, V. E., Madden, S. L., Zhang, L., Lash, A. E., Yu, J., Rago, C. et al. (1999). Analysis of human transcriptomes. Nat Genet, 23(4), 387-388.
Venturelli, S., Berger, A., Böcker, A., Busch, C., Weiland, T., Noor, S. et al. (2013). Resveratrol as a Pan-HDAC Inhibitor Alters the Acetylation Status of Jistone Proteins in Human-Derived Hepatoblastoma Cells. PLoS ONE, 8(8), e73097.
Violette, S., Poulain, L., Dussaulx, E., Pepin, D., Faussat, A.-M., Chambaz, J. et al. (2002). Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-XL in addition to Bax and p53 status. Int J Cancer, 98(4), 498-504.
Vogel, C. L., Cobleigh, M. A., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L. et al. (2002). Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol, 20(3), 719-726.
Vu, T., & Claret, F. X. (2012). Trastuzumab: Updated Mechanisms of Action and Resistance in Breast Cancer. Front Oncol, 2, 62.
Vucic, D., Dixit, V. M., & Wertz, I. E. (2011). Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol, 12(7), 439-452.
Wang, H., Zhang, H., Tang, L., Chen, H., Wu, C., Zhao, M. et al. (2013). Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis. Toxicology, 303, 139-146.
Wang, Y., Catana, F., Yang, Y., Roderick, R., & van Breemen, R. B. (2002). An LC-MS method for analyzing total resveratrol in grape juice, cranberry juice, and in wine. J Agric Food Chem, 50(3), 431-435.
Wolter, F., Akoglu, B., Clausnitzer, A., & Stein, J. (2001). Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell cycle arrest in colon cancer cell lines. J Nutr, 131(8), 2197-2203.
Wu, J. M., & Hsieh, T. C. (2011). Resveratrol: a cardioprotective substance. Ann N Y Acad Sci, 1215, 16-21.
Wu, S. L., Sun, Z. J., Yu, L., Meng, K. W., Qin, X. L., & Pan, C. E. (2004). Effect of resveratrol and in combination with 5-FU on murine liver cancer. World J Gastroenterol, 10(20), 3048-3052.
Xu, R., Zhang, P., Huang, J., Ge, S., Lu, J., & Qian, G. (2007). Sp1 and Sp3 regulate basal transcription of the survivin gene. Biochem Biophys Res Commun, 356(1), 286-292.
Yang, G., Nowsheen, S., Aziz, K., & Georgakilas, A. G. (2013). Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther, 139(3), 392-404.
Yang, Y. L., & Li, X. M. (2000). The IAP family: endogenous caspase inhibitors with multiple biological activities. Cell Res, 10(3), 169-177.
Zaffaroni, N., Pennati, M., Colella, G., Perego, P., Supino, R., Gatti, L. et al. (2002). Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci, 59(8), 1406-1412.
Zhang, L., Zhang, W., Wang, Y. F., Liu, B., Zhang, W. F., Zhao, Y. F. et al.. (2015). Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma. Cell Death Dis, 6, e1771.
Zhang, M., Coen, J. J., Suzuki, Y., Siedow, M. R., Niemierko, A., Khor, L. Y. et al. (2010). Survivin is a potential mediator of prostate cancer metastasis. Int J Radiat Oncol Biol Phys, 78(4), 1095-1103.
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