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研究生:黃靜如
研究生(外文):Cheng-ju Huang
論文名稱:CaffeicAcidPhenethylEster對於人類非小細胞肺癌H460及其太平洋紫杉醇抗藥性亞株H460/TAX的抗藥性削弱效應
論文名稱(外文):The Modulatory Effect of Caffeic Acid Phenethyl Ester (CAPE) on a Human Non-Small Cell Lung Cancer Cell Line parental H460 and It’s Paclitaxel Resistant Mutant.
指導教授:黎耀基黎耀基引用關係
指導教授(外文):Yiu-Kay Lai
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:41
中文關鍵詞:紫杉醇
外文關鍵詞:paclitaxel
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太平洋紫杉醇(paclitaxel)是非小細胞肺癌(non-small cell lung cancer)治療的化療藥劑之一,然而抗藥性的問題仍是臨床上亟待克服的瓶頸。我們先前以人類非小細胞肺癌細胞株H460 細胞為對象,建立了抗藥性亞株H460/TAX作為探討肺癌抗藥性機制及克服抗藥性的工具。Nuclear Factor kB (NF-kB)的活化是細胞受到藥物毒殺壓力下,細胞抵抗藥物毒性的反應。NF-kB的活化與誘發性抗藥性有關,許多抗癌藥物都會誘使NF-kB活化,而紫杉醇也是其中一種。壓抑NF-kB的活化可以加強細胞對化學療法的敏感度,以達到降低細胞抗藥性的效果。本實驗中我們研究Caffeic acid phenethyl ester (CAPE)減弱H460/TAX對紫杉醇的抗藥性的機制。CAPE是蜂膠中的一種活性成分,具有抗氧化,抗癌,抗病毒的功效,同時也是NF-kB 的抑制劑。我們發現對H460/TAX細胞做高濃度短時間的CAPE(25 mM, 2 days)前處理使H460/TAX細胞的抗藥性由29.73倍降至4.99倍,而低濃度長時間CAPE (5 mM, 7 days)的前處理使H460/TAX細胞的抗藥性由6.27倍降至1.83倍。高濃度短時間的CAPE前處理對於H460細胞有毒性,而低濃度長時間CAPE的前處理降低H460/TAX的抗藥性且不會對H460 細胞產生毒性。H460/TAX細胞本身具有較高含量的p65以及較低含量的IKBa。我們的結果顯示NF-kB參與H460/TAX細胞抗藥性。另外我們也證明了對H460/TAX細胞做CAPE的前處理可以降低紫杉醇引起的NF-kB活化。CAPE的前處理能抑制H460/TAX細胞對於紫杉醇的抗藥性。本實驗中提出H460/TAX細胞的NF-kB 活性參與了對紫杉醇的抗藥性。經由CAPE降低NF-kB的活化可進一步用來當作降低H460/TAX 細胞抗藥性的策略,而CAPE能協助紫杉醇化療過程中抗藥性的降低。

Acquired resistance to chemotherapy of anticancer drug paclitaxel is the problem during cancer treatment. To investigate the drug resistance, we established a paclitaxel-resistant mutant cell line called H460/TAX cells derived from human non-small cell lung cancer parental H460 cells. Nuclear factor kB (NF-kB) activation is associated with inducible chemoresistance. Many anti-cancer drugs are able to activate NF-kB. Paclitaxel is also one of anti-neoplastic drugs that activate NF-kB. Inhibition of NF-kB could sensitize cell to chemotherapy-induced apoptosis. Here, we examined the effect of caffeic acid phenethyl ester (CAPE) on paclitaxel resistance. CAPE, an active ingredient of propolis from honeybee hives, is known to have anti-inflammatory, anti-virus and anti-cancer properties. CAPE is a modulator capable of preventing the translocation of the p65 subunit of NF-kB to the nucleus. Recently, we found that pretreated cancer cells with CAPE (5 mM, 7 days) could decrease the drug resistance of mutant H460/TAX cells from 6.27 fold to 1.83 fold. Partial toxicity is found as the higher dose of CAPE; therefore, the low dose and long term CAPE pretreatment recover the drug sensitivity of mutant H460/TAX cells without poisoning the parental H460 cells. Mutant H460/TAX cells show higher p65 (subunit of NF-kB) and lower level of IKBa than parental H460 cells. Decreasing of resistance in mutant H460/TAX cells by the pretreatment of CAPE also reduces the paclitaxel induced NF-kB activation. Taken together, our results support the involvement of NF-kB in paclitaxel induced resistance, and CAPE is a potent modulator of NF-kB activity to improve the clinical efficacy of paclitaxel in lung cancer treatment.

目 錄
一、中文摘要-------------------------------------------------2
二、英文附錄
1. Abstract-----------------------------------------3
2. Abbreviation-----------------------------------4
3. Introduction------------------------------------5
4. Materials and Methods----------------------8
5. Results------------------------------------------13
6. Discussion--------------------------------------18
7. Figures and Figure Legends---------------22
8. References-------------------------------------35

1. Wani MC, T. H., Coggon P and McPhail AT. Plant antimumor agents Ⅵ: The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxu brivifili., J. Am. Chem. Soc. 93: 2325-2327, 1971.
2. RK., F. D. a. J. Cytologic evidence that paclitaxel, an antineoplastic agent frome Taxu brivifili acts as mitotic spindle poison., Cancer Treat Rep. 62: 1219-1222, 1978.
3. Fan, W. Possible mechanisms of paclitaxel-induced apoptosis, Biochem Pharmacol. 57: 1215-21., 1999.
4. Jordan, M. A., Toso, R. J., Thrower, D., and Wilson, L. Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations, Proc Natl Acad Sci U S A. 90: 9552-6., 1993.
5. Lieu, C. H., Chang, Y. N., and Lai, Y. K. Dual cytotoxic mechanisms of submicromolar taxol on human leukemia HL- 60 cells, Biochem Pharmacol. 53: 1587-96., 1997.
6. Torres, K. and Horwitz, S. B. Mechanisms of Taxol-induced cell death are concentration dependent, Cancer Res. 58: 3620-6., 1998.
7. Wang, T. H., Wang, H. S., and Soong, Y. K. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together, Cancer. 88: 2619-28., 2000.
8. Ling, Y. H., Tornos, C., and Perez-Soler, R. Phosphorylation of Bcl-2 is a marker of M phase events and not a determinant of apoptosis, J Biol Chem. 273: 18984-91., 1998.
9. Kavallaris, M., Kuo, D. Y., Burkhart, C. A., Regl, D. L., Norris, M. D., Haber, M., and Horwitz, S. B. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes, J Clin Invest. 100: 1282-93., 1997.
10. Monzo, M., Rosell, R., Sanchez, J. J., Lee, J. S., O'Brate, A., Gonzalez-Larriba, J. L., Alberola, V., Lorenzo, J. C., Nunez, L., Ro, J. Y., and Martin, C. Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations, J Clin Oncol. 17: 1786-93., 1999.
11. Ibrado, A. M., Liu, L., and Bhalla, K. Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells, Cancer Res. 57: 1109-15., 1997.
12. Lebedeva, I., Rando, R., Ojwang, J., Cossum, P., and Stein, C. A. Bcl-xL in prostate cancer cells: effects of overexpression and down- regulation on chemosensitivity, Cancer Res. 60: 6052-60., 2000.
13. Miyake, H., Monia, B. P., and Gleave, M. E. Inhibition of progression to androgen-independence by combined adjuvant treatment with antisense BCL-XL and antisense Bcl-2 oligonucleotides plus taxol after castration in the Shionogi tumor model, Int J Cancer. 86: 855-62., 2000.
14. Chu, J. J., Chiang, C. D., Rao, C. S., Chang, W. M., and Lai, Y. K. Establishment and characterization of a paclitaxel-resistant human non- small cell lung cancer cell line, Anticancer Res. 20: 2449-56., 2000.
15. Hwang, S. and Ding, A. Activation of NF-kappa B in murine macrophages by taxol, Cancer Biochem Biophys. 14: 265-72., 1995.
16. Das, K. C. and White, C. W. Activation of NF-kappaB by antineoplastic agents. Role of protein kinase C, J Biol Chem. 272: 14914-20., 1997.
17. Foo, S. Y. and Nolan, G. P. NF-kappaB to the rescue: RELs, apoptosis and cellular transformation, Trends Genet. 15: 229-35. _00001719 _00001719, 1999.
18. Wang, C. Y., Mayo, M. W., and Baldwin, A. S., Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB, Science. 274: 784-7., 1996.
19. Arlt, A., Vorndamm, J., Breitenbroich, M., Folsch, U. R., Kalthoff, H., Schmidt, W. E., and Schafer, H. Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin, Oncogene. 20: 859-68, 2001.
20. Wang, C. Y., Cusack, J. C., Jr., Liu, R., and Baldwin, A. S., Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB, Nat Med. 5: 412-7, 1999.
21. Cusack, J. C., Jr., Liu, R., and Baldwin, A. S., Jr. Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]- carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation, Cancer Res. 60: 2323-30., 2000.
22. Fesen, M. R., Pommier, Y., Leteurtre, F., Hiroguchi, S., Yung, J., and Kohn, K. W. Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds, Biochem Pharmacol. 48: 595-608., 1994.
23. Bhimani, R. S., Troll, W., Grunberger, D., and Frenkel, K. Inhibition of oxidative stress in HeLa cells by chemopreventive agents, Cancer Res. 53: 4528-33, 1993.
24. Grunberger, D., Banerjee, R., Eisinger, K., Oltz, E. M., Efros, L., Caldwell, M., Estevez, V., and Nakanishi, K. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis, Experientia. 44: 230-2., 1988.
25. Su, Z. Z., Lin, J., Grunberger, D., and Fisher, P. B. Growth suppression and toxicity induced by caffeic acid phenethyl ester (CAPE) in type 5 adenovirus-transformed rat embryo cells correlate directly with transformation progression, Cancer Res. 54: 1865-70., 1994.
26. Su, Z. Z., Lin, J., Prewett, M., Goldstein, N. I., and Fisher, P. B. Apoptosis mediates the selective toxicity of caffeic acid phenethyl ester (CAPE) toward oncogene-transformed rat embryo fibroblast cells, Anticancer Res. 15: 1841-8., 1995.
27. Chen, J. H., Shao, Y., Huang, M. T., Chin, C. K., and Ho, C. T. Inhibitory effect of caffeic acid phenethyl ester on human leukemia HL- 60 cells, Cancer Lett. 108: 211-4., 1996.
28. Lee, Y. J., Liao, P. H., Chen, W. K., and Yang, C. Y. Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells, Cancer Lett. 153: 51-6., 2000.
29. Frenkel, K., Wei, H., Bhimani, R., Ye, J., Zadunaisky, J. A., Huang, M. T., Ferraro, T., Conney, A. H., and Grunberger, D. Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester, Cancer Res. 53: 1255-61., 1993.
30. Chiao, C., Carothers, A. M., Grunberger, D., Solomon, G., Preston, G. A., and Barrett, J. C. Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells, Cancer Res. 55: 3576-83., 1995.
31. Chen, Y. J., Shiao, M. S., and Wang, S. Y. The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells, Anticancer Drugs. 12: 143-9., 2001.
32. Nomura, M., Kaji, A., Ma, W., Miyamoto, K., and Dong, Z. Suppression of cell transformation and induction of apoptosis by caffeic acid phenethyl ester, Mol Carcinog. 31: 83-9., 2001.
33. Ozyurt, H., Irmak, M. K., Akyol, O., and Sogut, S. Caffeic acid phenethyl ester changes the indices of oxidative stress in serum of rats with renal ischaemia-reperfusion injury, Cell Biochem Funct. 19: 259-63., 2001.
34. Weyant, M. J., Carothers, A. M., Bertagnolli, M. E., and Bertagnolli, M. M. Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways, Clin Cancer Res. 6: 949-56., 2000.
35. Na, H. K., Wilson, M. R., Kang, K. S., Chang, C. C., Grunberger, D., and Trosko, J. E. Restoration of gap junctional intercellular communication by caffeic acid phenethyl ester (CAPE) in a ras-transformed rat liver epithelial cell line, Cancer Lett. 157: 31-8., 2000.
36. Chen, Y. J., Shiao, M. S., Hsu, M. L., Tsai, T. H., and Wang, S. Y. Effect of caffeic acid phenethyl ester, an antioxidant from propolis, on inducing apoptosis in human leukemic HL-60 cells, J Agric Food Chem. 49: 5615-9., 2001.
37. Mahmoud, N. N., Carothers, A. M., Grunberger, D., Bilinski, R. T., Churchill, M. R., Martucci, C., Newmark, H. L., and Bertagnolli, M. M. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis, Carcinogenesis. 21: 921-7, 2000.
38. Natarajan, K., Singh, S., Burke, T. R., Jr., Grunberger, D., and Aggarwal, B. B. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B, Proc Natl Acad Sci U S A. 93: 9090-5., 1996.
39. Haddad, J. J. and Fahlman, C. S. Nuclear factor-kappa B-independent regulation of lipopolysaccharide- mediated interleukin-6 biosynthesis, Biochem Biophys Res Commun. 291: 1045-51., 2002.
40. Kim, J. Y., Lee, S., Hwangbo, B., Lee, C. T., Kim, Y. W., Han, S. K., Shim, Y. S., and Yoo, C. G. NF-kappaB activation is related to the resistance of lung cancer cells to TNF-alpha-induced apoptosis, Biochem Biophys Res Commun. 273: 140-6, 2000.
41. Baldwin, A. S. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB, J Clin Invest. 107: 241-6, 2001.
42. Spencer, W., Kwon, H., Crepieux, P., Leclerc, N., Lin, R., and Hiscott, J. Taxol selectively blocks microtubule dependent NF-kappaB activation by phorbol ester via inhibition of IkappaBalpha phosphorylation and degradation, Oncogene. 18: 495-505., 1999.
43. Patel, N. M., Nozaki, S., Shortle, N. H., Bhat-Nakshatri, P., Newton, T. R., Rice, S., Gelfanov, V., Boswell, S. H., Goulet, R. J., Jr., Sledge, G. W., Jr., and Nakshatri, H. Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide, Oncogene. 19: 4159-69., 2000.
44. Huang, Y., Johnson, K. R., Norris, J. S., and Fan, W. Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells, Cancer Res. 60: 4426-32., 2000.
45. Weldon, C. B., Burow, M. E., Rolfe, K. W., Clayton, J. L., Jaffe, B. M., and Beckman, B. S. NF-kappa B-mediated chemoresistance in breast cancer cells, Surgery. 130: 143-50. t&artType=abs&id=a115512&target=, 2001.
46. Huisman, C., Ferreira, C. G., Broker, L. E., Rodriguez, J. A., Smit, E. F., Postmus, P. E., Kruyt, F. A., and Giaccone, G. Paclitaxel Triggers Cell Death Primarily via Caspase-independent Routes in the Non-Small Cell Lung Cancer Cell Line NCI-H460, Clin Cancer Res. 8: 596-606., 2002.
47. Lieu, C. H., Liu, C. C., Yu, T. H., Chen, K. D., Chang, Y. N., and Lai, Y. K. Role of mitogen-activated protein kinase in taxol-induced apoptosis in human leukemic U937 cells, Cell Growth Differ. 9: 767-76., 1998.
48. Shtil, A. A., Mandlekar, S., Yu, R., Walter, R. J., Hagen, K., Tan, T. H., Roninson, I. B., and Kong, A. N. Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells, Oncogene. 18: 377-84., 1999.
49. MacKeigan, J. P., Collins, T. S., and Ting, J. P. MEK inhibition enhances paclitaxel-induced tumor apoptosis, J Biol Chem. 275: 38953-6., 2000.
50. Bacus, S. S., Gudkov, A. V., Lowe, M., Lyass, L., Yung, Y., Komarov, A. P., Keyomarsi, K., Yarden, Y., and Seger, R. Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53, Oncogene. 20: 147-55., 2001.
51. Chuang, S.-E., Yeh, P.-Y., Lu, Y.-S., Lai, G.-M., Liao, C.-M., Gao, M., and Cheng, A.-L. Basal level and patterns of anticancer drug-induced activation of nuclear factor kB (NF-kB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinima cells, Biochemical Pharmacology. 63: 1709-1716, 2002.
52. Mayo, M. W. and Baldwin, A. S. The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance, Biochim Biophys Acta. 1470: M55-62., 2000.
53. Rao, C. V., Rivenson, A., Simi, B., and Reddy, B. S. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound, Cancer Res. 55: 259-66., 1995.

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