Microtubule damaging agents (such as paclitaxel and nocodazole (ND)) have been used in the clinical cancer chemotherapy. However, the molecular mechanisms of these agents in the induction of anti-cancer activity are still unclear. In the present study, we demonstrated that 0.2 muM podophyllotoxin (PDP) induced the occurrence of apoptosis in human leukemic (HL 60) cells and cell cycle arrest at the G2/M phase in HT 29 cells. Our results suggest that the PDP-induced G2/M arrest in HT 29 cells was through the intracellular events including (a) inhibition of normal mitotic spindle formation, (b) elevation of cyclin B1/cdc2 kinase activity, (c) concomitant increases in cdc 25 A phosphatase and cdk 7 kinase activity, and (d) down-regulation of the wee-1 protein expression. On the other hand. activations of the caspases 3. 8. and 9, Bcl-2 hyper-phosphorylation, and increased leakage of cytochrome c from mitochondria into cytosolic fraction were detected in the PDP-treated HL 60 cells. These listed intracellular events were interpreted to lead to the apoptosis observed in PDP-treated HL 60 cells. We further demonstrated that activation of c-jun N-terminal kinase (JNK) signaling pathway may play an important role in the PDP-induced Bcl-2 phosphorylation and apoptosis in HL 60 cells as evidenced by the JNK specific anti-sense oligonucleotide experiment. Our results demonstrated that the occurrence of apoptosis or G2/M cell cycle arrest induced by microtubule damaging agents in different cancer cells was through independent mechanisms. The results from the present study highlight the molecular mechanisms underlying of the PDP-induced anti-cancer activity. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
机构:
China Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
Fushun Min Bur, Dept Circulatory, Gen Hosp, Fushun 113008, Liaoning, Peoples R ChinaChina Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
Lin, Jihong
Zhang, Lei
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China Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R ChinaChina Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
Zhang, Lei
Wang, Zhiwei
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Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R ChinaChina Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
Wang, Zhiwei
Guan, Qi
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Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R ChinaChina Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
Guan, Qi
Bao, Kai
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Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R ChinaChina Med Univ, Affiliated Hosp 1, Dept Geratol, 155 Nanjing St, Shenyang 110001, Liaoning, Peoples R China
机构:
Konkuk Univ, Res Ctr Transcript Control, Seoul 143701, South KoreaKonkuk Univ, Dept Biomed Sci & Technol, IBST, Seoul 143701, South Korea
Shin, Soon Young
Yong, Yeonjoong
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Konkuk Univ, Div Biosci & Biotechnol, BMIC, Seoul 143701, South KoreaKonkuk Univ, Dept Biomed Sci & Technol, IBST, Seoul 143701, South Korea
Yong, Yeonjoong
Kim, Chang Gun
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Konkuk Univ, Res Ctr Transcript Control, Seoul 143701, South KoreaKonkuk Univ, Dept Biomed Sci & Technol, IBST, Seoul 143701, South Korea
Kim, Chang Gun
Lee, Young Han
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Konkuk Univ, Dept Biomed Sci & Technol, IBST, Seoul 143701, South Korea
Konkuk Univ, Res Ctr Transcript Control, Seoul 143701, South KoreaKonkuk Univ, Dept Biomed Sci & Technol, IBST, Seoul 143701, South Korea
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Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
Duan, Fang-Fang
Liu, Lin
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Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
Liu, Lin
Gao, Ying
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Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
Gao, Ying
Peng, Xiao-Gang
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Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
Peng, Xiao-Gang
Meng, Xiang-Gao
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Cent China Normal Univ, Coll Chem, Wuhan 430079, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
Meng, Xiang-Gao
Ruan, Han-Li
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Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R ChinaHuazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China
机构:
Suzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Li, Yongjian
Wang, Xiaorong
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Suzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R China
Nanjing Univ Chinese Med, Clin Med Coll 1, Nanjing 210046, Jiangsu, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Wang, Xiaorong
Cheng, Silu
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Cheng, Silu
Du, Juan
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Du, Juan
Deng, Zhengting
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Suzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Deng, Zhengting
Zhang, Yani
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Zhang, Yani
Liu, Qun
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Liu, Qun
Gao, Jingdong
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Suzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Gao, Jingdong
Cheng, Binbin
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
Cheng, Binbin
Ling, Changquan
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Second Mil Med Univ, Changhai Hosp, Dept Tradit Chinese Med, Shanghai 200433, Peoples R China
Shanghai Municipal Educ Commiss, E Inst TCM Internal Med, Shanghai 201203, Peoples R ChinaSuzhou Hosp Tradit Chinese Med, Dept Oncol, Suzhou 215009, Jiangsu, Peoples R China
机构:
Taichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Chung Shan Med Univ, Inst Med, Taichung 40201, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Yuan, Sheau-Yun
Lin, Chi-Chen
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Taichung Vet Gen Hosp, Dept Educ & Res, Taichung 40705, Taiwan
Natl Chung Hsing Univ, Inst Biomed Sci, Taichung 40227, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Lin, Chi-Chen
Hsu, Shih-Lan
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Taichung Vet Gen Hosp, Dept Educ & Res, Taichung 40705, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Hsu, Shih-Lan
Cheng, Ya-Wen
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Chung Shan Med Univ, Inst Med, Taichung 40201, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Cheng, Ya-Wen
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Wu, Jyh-Horng
Cheng, Chen-Li
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Taichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan
Cheng, Chen-Li
Yang, Chi-Rei
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Taichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, TaiwanTaichung Vet Gen Hosp, Dept Surg, Div Urol, Taichung 40705, Taiwan