Amyrin esters induce cell death by apoptosis in HL-60 leukemia cells

Four derivatives of an alpha,beta-amyrin mixture were synthesized by acylation with appropriate anhydrides. The structures of the compounds were confirmed by means of IR and H-1 and C-13 NMR. The compounds were screened for cytotoxic activity using four human tumor cell lines (HL-60, MDAMB-435, SF-295 and HCT-8) and normal peripheral blood mononuclear cells (PBMC). 3-O-Carboxymaleinate of alpha,beta-amyrin (3a/3b) were found to be the only active compounds of the series (high cytotoxicity), showing IC50 values ranging from 1.8 to 3 mu M. In PBMC, 3a/3b were not toxic, suggesting selectivity for tumor cells. To better understand the mechanism of action involved in the cytotoxicity of 3a/3b, HL-60 cells treated with 3a/3b were examined for morphological changes, DNA fragmentation, cell cycle perturbation, externalization of phosphatidylserine and activation of caspases 3/7, with doxorubicin serving as the positive control. The results indicate that the cytotoxicity of 3a/3b involves the induction of cell death by apoptosis. (C) 2010 Elsevier Ltd. All rights reserved.