Activation of JNK Contributes to Evodiamine-Induced Apoptosis and G2/M Arrest in Human Colorectal Carcinoma Cells: A Structure-Activity Study of Evodiamine

被引:64
作者
Chien, Chih-Chiang [1 ,2 ]
Wu, Ming-Shun [3 ]
Shen, Shing-Chuan [4 ]
Ko, Ching-Huai [5 ,6 ]
Chen, Chih-Hung [5 ,6 ]
Yang, Ling-Ling [7 ]
Chen, Yen-Chou [4 ,8 ,9 ]
机构
[1] Chi Mei Med Ctr, Dept Nephrol, Tainan, Taiwan
[2] Chung Hwa Univ Med Technol, Dept Food Nutr, Tainan, Taiwan
[3] Taipei Med Univ, Wan Fang Hosp, Dept Internal Med, Div Gastroenterol, Taipei, Taiwan
[4] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan
[5] Ind Technol Res Inst, Strateg Business & Innovat Technol Dev Div, Hsinchu, Taiwan
[6] Ind Technol Res Inst, Biomed Technol & Device Res Labs, Hsinchu, Taiwan
[7] Fo Guang Univ, Coll LOHAS, Yilan, Taiwan
[8] Taipei Med Univ Hosp, Canc Res Ctr, Taipei, Taiwan
[9] Taipei Med Univ Hosp, Orthoped Res Ctr, Taipei, Taiwan
关键词
BREAST-CANCER CELLS; INDEPENDENT APOPTOSIS; ROS; INHIBITION; PHOSPHORYLATION; TELOMERASE; PATHWAY; GROWTH; BINDS;
D O I
10.1371/journal.pone.0099729
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2'3'-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism is still unclear. In this study, we investigated the anticancer effects of EVO on human colon COLO205 and HT-29 cells and their potential mechanisms. MTT and lactate dehydrogenase (LDH) release assays showed that the viability of COLOL205 and HT-29 cells was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells and cleavage of caspase-3 and poly(ADP ribose) polymerase (PARP) proteins. Disruption of the mitochondrial membrane potential by EVO was accompanied by increased Bax, caspase-9 protein cleavage, and cytochrome (Cyt) c protein translocation in COLO205 and HT-29 cells. Application of the antioxidant N-acetyl-L-cysteine (NAC) inhibited H2O2-induced reactive oxygen species (ROS) production and apoptosis, but did not affect EVO-induced apoptosis of COLO205 or HT-29 cells. Significant increases in the G(2)/M ratio and cyclinB1/cdc25c protein expression by EVO were respectively identified in colon carcinoma cells via a flow cytometric analysis and Western blotting. Induction of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) protein phosphorylation was detected in EVO-treated cells, and the JNK inhibitor, SP600125, but not the ERK inhibitor, U0126, inhibited EVO-induced phosphorylated JNK protein expression, apoptosis, and G(2)/M arrest of colon carcinoma cells. Data of the structure-activity analysis showed that EVO-related chemicals containing an alkyl group at position 14 were able to induce apoptosis, G(2)/M arrest associated with increased DNA ladder formation, cleavage of caspase-3 and PARP, and elevated cycB1 and cdc25c protein expressions in COLO205 and HT-29 cells. Evidence supporting JNK activation leading to EVO-induced apoptosis and G(2)/M arrest in colon carcinoma cells is provided, and alkylation at position 14 of EVO is a critical substitution for treatment of colonic cancer.
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页数:12
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