Cell Cycle Arrest and Apoptosis Induction by an Anticancer Chalcone Epoxide

被引:14
作者
Han, Haiyong [1 ]
Zhao, Yu [1 ]
Cuthbertson, Timothy [2 ,3 ]
Hartman, Rosemarie F. [2 ]
Rose, Seth D. [2 ]
机构
[1] Translat Genom Res Inst, Phoenix, AZ 85004 USA
[2] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ USA
[3] Targacept, Winston Salem, NC USA
关键词
Apoptosis; Cell cycle arrest; Chalcone epoxide; Pancreatic cancer; BIOLOGICAL EVALUATION; BETA-TUBULIN; INHIBITORS; BINDING;
D O I
10.1002/ardp.200900261
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Safe and effective chemotherapeutic agents for the treatment of pancreatic cancer remain elusive. We found that chalcone epoxides (1,3-diary1-2,3-epoxypropanones) inhibited growth in two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2. Three compounds were active, with GI(50) values of 5.6 to 15.8 mu M. Compound 4a, 1,3-bis-(3,4,5-trimethoxyphenyl)-2,3-epoxypropanone, had an average GI(50) of 14.1 mu M in the NCI 60-cell-line panel. To investigate the mode of action, cell cycle analyses of BxPC-3 cells were carried out. Treatment of cells with 50 mu M 4a resulted in dramatic accumulation at G2/M (61% after 12 h for 4a vs. 15% for untreated cells). The cells rapidly entered apoptosis. After 12 h, 26% of cells treated with 50 mu M 4a had entered apoptosis vs. 4% for cells treated with 100 mu M etoposide and 2% for untreated cells. Compound 4a interfered with paclitaxel enhancement of tubulin polymerization, suggesting microtubules as the site of action. Reaction of thiol nucleophiles with 4a under basic conditions resulted in epoxide ring-opening and retroaldol fragmentation, yielding alkylated thiol. MALDI mass spectrometry showed that retroaldol reaction occurred upon treatment of beta-tubulin with 4a. The site of alkylation was identified as Cys(354). Chalcone epoxides warrant further study as potential agents for treatment of cancer.
引用
收藏
页码:429 / 439
页数:11
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