Cell cycle arrest and apoptosis induction by an anticancer chalcone epoxide

Safe and effective chemotherapeutic agents for the treatment of pancreatic cancer remain elusive. We found that chalcone epoxides (1,3-diaryl-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 microM. Compound 4a, 1,3-bis-(3,4,5-trimethoxyphenyl)-2,3-epoxypropanone, had an average GI(50) of 14.1 microM 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 microM 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 microM 4a had entered apoptosis vs. 4% for cells treated with 100 microM 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.