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研究生:儲天輝
研究生(外文):Tian-huei Chu
論文名稱:Celecoxib對Novikoff原位肝癌的治療效應
論文名稱(外文):Therapeutic Efficacy of Celecoxib for Orthotopic Novikoff Hepatoma
指導教授:戴明泓
指導教授(外文):Ming-Hong Tai
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
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:2009
畢業學年度:97
語文別:英文
論文頁數:64
中文關鍵詞:原位肝癌第二型環氧化酵素超音波
外文關鍵詞:Orthotopic hepatocellular carcinomaCOX2Ultrasound
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肝細胞肝癌是一種死亡率非常高的癌症,它的致死率是再癌症中排名第三位. 常見的治療方式有手術切除和經動脈栓塞,而且一般常見的化療藥物有epirubicin, doxorubicin, cisplatin and 5-FU, 但是治療效果往往不是很好,而且化療藥物對患者會產生極大的副作用, 例如: 掉頭髮,嘔吐. 這些化療藥物在臨床上沒有很好的抗肝癌效果, 在我們之前的研究中我們發現epirubicin對大鼠的原位肝癌的腫瘤大小有抑制的效果,但是我們發現epirubicin對大鼠本身會造成極大的副作用,例如: 掉毛, 體重下降, 脾臟變小, 白血球數目下降, GOT上升. 所以我們想要利用一些低毒性的臨床用藥來治療原位肝癌,像celecoxib就是一種毒性低的臨床用藥,它本身是一個第二型環氧化酵素 (COX-2) 的抑制劑,而且毒性也比傳統的非類固醇抗發炎藥物來的低, 而且專一性非常的高, 而且在我們的實驗中我們發現N1-S1肝癌細胞株和Clone 9正常肝細胞株中所測得的半抑制劑量是100 microM, 而且我們發現N1-S1肝癌細胞株的 COX-2蛋白質表現量和mRNA表現量是非常低的, 所以N1-S1細胞是一種COX-2表現量非常低的肝癌細胞株, 但有趣的是我們發現celecoxib在細胞實驗中可以經由COX-2 independent的作用機轉去正調控PPAR-gamma和PTEN的表現,進而使得AKT的磷酸化比例下降,而且我們每天餵食celecoxib (30mg/kg/rat)且連續餵食七天,治療過後我們不管用超音波還是電腦斷層掃描, 我們都可以看出celecoxib在活體中對肝腫瘤我抑制的效果, 而且我們發現治療組大鼠的肝組織中CD-31有變少的趨勢,這也代表celecoxib在活體中具有抑制腫瘤血管新生的效果,在者,我們發現celecoxib在活體中可以減少Ki-67的表現量,這代表癌細胞的增生速度減緩,以及看見治療組中的TUNEL增加,這表示癌細胞細胞凋亡的比例提高。在免疫系統方面,我們發現治療組可以減少FOXP3在腫瘤週遭的比例,所以celecoxib有破壞癌細胞逃脫免疫系統機轉的潛力 除此之外, 在動物實驗中我們發現celecoxib對動物本身沒有明顯的副作用,所以我們認為celecoxib是一個適合與epirubicin或是其他化療藥物組合使用的輔助抗肝腫瘤藥劑。
Hepatocellular carcinoma (HCC) is one of deadliest cancers worldwide and ranking the third among all cancer-related mortalities. Current effective therapeutic approaches for HCC include surgical resection and trans-arterial embolization (TAE). Chemotherapy remains largely ineffective, and most popular used agents are epirubicin, doxorubicin, cisplatin and 5-FU. Besides, these chemotherapic drugs had potential serious side-effects such as low blood count, hair loss, vomiting, and they rarely present good anti-HCC effect in clinical practice. Our previous studies found that epirubicin injection attenuated the tumor burden of orthotopic Novikoff hepatoma, but caused serious side effects to hosts including reduction in spleen weight, white count, and body weight and high GOT level. Therefore, we aimed to evaluate possible alternative treatment such as COX-2 inhibitor for HCC. Celecoxib is a highly selective COX-2 inhibitor and less toxic than the traditional non-selective NSAIDs. Celecoxib showed relatively low cytotoxicity in Novikoff N1-S1 hepatoma cells and Clone 9 normal hepatocytes with an IC50 of up to 100 microM. Expression analysis revealed that COX-2 expression is very low in N1-S1 cells at protein and mRNA levels. Thus, N1-S1 is a kind of hepatoma cell line with low COX-II level. Interestingly, celecoxib upregulated PTEN expression and decreased AKT phosphorylation in vitro by COX-2 independent pathway, and then oral administration of celecoxib (30 mg/kg) for 7 days showed tendency of tumor suppression of Novikoff hepatoma in rats revealed by ultrasound and computed tomography (CT) scan. Histological analysis revealed that CD31-positive neo-vascularization、Ki-67-positive cell-proliferation and FOXP3-positive regulatory T cells were found to reduce in celecoxib-treated rats, and then TUNEL-positive apoptotic cells were found to increase in celecoxib-treated rats. Besides, celecoxib-treated rats exhibited no significant side effect. Therefore, oral celecoxib may be a suitable chose of adjuvant therapy in combination with epirubicin or other chemotherapeutic agents for the treatment of HCC.
Abbreviations 4
Abstract in Chinese 5~6
Abstract in Englis 7~8
Introduction 9~11
Materials and Methods 12~17
Results 18~25
Discussion 26~28
References 29~34
Figures and Legends 35~58
Appendix 59~64
1. KewMC. Hepatic tumors and cysts. In: Feldman M, SleisengerMH, Scharschmidt BF. Gastro- intestinal and liver disease. 6th ed. Philadelphia: WB Saunders;1998. p.1364-87.
2. El-Serag HB, Mason A. Rising incidence of hepatocellular carcinoma in the United States. N Engl JMed 1999;340:745-50
3. El-Serag HB, Mason A, Key C. Trends in survival of patients with hepatocellular carcinoma between 1997 and 1996 in the United States. Hepatology 2001; 33:62-5.
4. Willams CS, Mann M, DuBois RN. The role of cyclooxygenase in inflammation, cancer and development. Oncology1999;18:7908-16.
5. Hu K-Q. Rationale and feasibility of chemoprevention of hepatocellular carcinoma by cyclo- oxygenase-2 inhibitors. Lab ClinMed 2002;139:234-43.
6. Fosslien E. Biochemistry of cyclooxygenase (COX-2) inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000;37:431-502
7. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2
Inhumanhepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 1999;29:688-96.
8. Kondo M,Yamamoto H, Nagano H, et al. Increased expression of COX-2 innontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res 1999;5: 4005-12
9.Fosslien E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000;37:431–502
10. Hu K-Q, Yu C-H, Mineyama Y, McCrachen JD, Hillebrand DJ, Hasan M. Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor. Int J Oncol 2003;22:757-63.
11. Bae SH, Jung ES, ParkYM, et al. Expression of cyclooxygenase- 2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 2001;7: 1410 - 8.
12. KernMA, SchubertD, SahiD, et al. Proapoptotic and antiproliferative potential of selective cyclo- oxygenase- 2 inhibitors in human liver tumor cells. Hepatology 2000;36:885-94.
13. Cheng ASL, Chan HY, LeungW,Wong N, Johnson PJ, Sung JY. Specific COX-2 inhibitor, NS-398, suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells. Int J Oncol 2003;23:113-9.
14.Wen B, Deutsch E, Eschwege P, et al. Cyclooxygenase- 2 inhibitor NS-398 enhances antitumor effect of irradiation on hormone refractory human prostate carcinoma cells. JUrol 2003;170: 2036-9.
15. Maier TJ, Schilling K, Schmidt R, Geisslinger G, Grosch S. Cyclooxygenase-2 (COX-2) dependent and independent anticarcinogenic effect of celecoxib in human colon carcinoma cells. Biochem Pharmacol 2004;69:1469-78.
16. Steinbach G, Lynch P, Phillips PKS, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342: 1946- 52.
17. Howe LR, Subbaromaiah K, Patel J, et al. Celecoxib, a selective cyclooxygenase-2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 2002;62:5405-7.
18. Zhang Z, Lai GH, Sirica A. Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated byAkt inactivation and Bax translocation. Hepatology 2004; 39:1028-37.
19. Orengo IF, Gergois J, Phillpis R, Guevara A, Lewis AT, Black HS. Celecoxib, a cyclooxygenase-2 inhibitor as a potential chemopreventive to UV-induced skin cancer. Arch Dermatol 2002;138: 751- 5.
20. Kern MA, Schubert D, Sahi D, et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 2002;36: 885–94.
21. Han C, LengJ,Demetris AJ,WuT. Cyclooxygenase- 2 promotes human cholangiocarcinomagrowth: evidence for cyclooxygenase-2-independentmechanism in celecoxib-mediated induction of p21waf1/cip1 and p27kip1 and cell cycle arrest. Cancer Res 2004; 64: 1369 - 76.
22.Wick M, Hurteau G, Dessev C, et al. Peroxisomeproliferator-activated receptor-g is a targetof nonsteroidal anti-inflammatory drugs mediating cyclooxygenaseindependent inhibition of lung cancer cell growth. Mol Pharmacol 2002;62: 1207-14.
23. Rahman MA, Kohno H, Nagasue N. COX-2 - a target for preventing hepatic carcinoma? Expert Opin Ther Targets. 2002 Aug;6(4):483-90. Review.
24. Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, Beauchamp RD, DuBois RN. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 1997;99:2254–9
25. Hsi LC, Baek SJ, Eling TE. Lack of cyclooxygenase-2 activity in HT-29 human colorectal carcinoma cells. Exp Cell Res 2000;256:563–70.
26. Shishodia S. and Aggarwal BB. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase
in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9. Cancer Res 2004;64:5004–12.
27. Jang MH, Shin MC, Lim S, Han SM, Park HJ, Shin I, Lee JS, Kim KA, Kim EH, Kim CJ. Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J Pharmacol Sci 2003;91:95–104.
28. Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 2001;15:2742–4.
29. Agarwal B, Bhendwal S, Halmos B, Moss SF, Ramey WG, Holt PR. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res 1999;5:2223–9.
30. Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF. Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study. Gastroenterology 2007;133:393–40.
31. Braun D, Longman RS, Albert ML. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendriticcell maturation. Blood. 2005;106:2375–2381.
32. Taylor MW, Feng GS. Relationship between interferongamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. Faseb J. 1991;5:2516–2522.
33. Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol. 2000;164: 361–370.
34. Thun, M.J., Henley, S.J., and Patrono, C. (2002). Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J. Natl. Cancer Inst. 94, 252–266.
35. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 1999; 29:688–696.
36. Bae SH, Jung ES, Park YM, et al. Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 2001;7: 1410–1418.
37. Shiota G, Okubo M, Noumi T, et al. Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterol 1999;46:407–412.
38. Kondo M, Yamamoto H, Nagano H, et al. Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res 1999;5:4005–4012.
39. Jonathan MB, Sarita GM, Lori LS, Nichole SB, Prabhat CG,Frederick ED, and Douglas KT. Celecoxib Toxicity Is Cell Cycle Phase Specific. Cancer Res 2007; 67: (8). April 15, 2007
40. Rosemary ET, Sarah MP, Kristin AW and Charis E Regulation of the PTEN promoter by statins and SREBP. Human Molecular Genetics, 2008, Vol. 17, No. 7
41. Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH, Fowble JW, Ward PJ, Chen CS. 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 2004;64: 1444–51.
42. Kim SH, Song SH, Kim SG, Chun KS, Lim SY, Na HK, Kim JW, Surh YJ, Bang YJ, Song YS. Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-kappaB as a possible target. J Cancer Res Clin Oncol 2004;130:551–60.
43. Stark LA, Din FV, Zwacka RM, Dunlop MG. Aspirin-induced activation of the NF-kappaB signaling pathway: a novel mechanism for aspirin-mediated apoptosis in colon cancer cells. FASEB J 2001;15: 1273–5.
44. Dihlmann S, Klein S, Doeberitz Mv MK. Reduction of beta-catenin/ T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin. Mol Cancer Ther 2003;2:509–16.
45. Lin HP, Kulp SK, Tseng PH, Yang YT, Yang CC, Chen CS, Che CS. Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms. Mol Cancer Ther 2004;3:1671–80.
46. Zheng X, Cui XX, Avila GE, Huang MT, Liu Y, Patel J, Kong AN, Paulino R, Shih WJ, Lin Y, Rabson AB, Reddy BS, et al. Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin Cancer Res 2007;13:5480–7.
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