Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines

Abstract

Breast cancer is the leading cause of cancer-related death in women worldwide and a critical public health concern. Here we investigated the anticancer potential and effects of low-molecular-weight bridgehead oxygen and nitrogen-containing spiro-bisheterocycles on proliferation and apoptosis of the human breast cancer cell lines MCF-7 and MDA-MB-231. The compounds feature a hydantoin moiety attached to either diazole, isoxazole, diazepine, oxazepine or benzodiazepine via the privileged tetrahedral spiro-linkage. Treatment with compounds spiro [hydantoin-isoxazole] and spiro [hydantoin-oxazepine] resulted in a dose-dependent decrease of cell proliferation and induction of apoptosis in both breast cancer cell lines, whereas spiro [hydantoin-diazepine] was only active against MDA-MB 231. Quantitative reverse transcription polymerase chain reaction analysis showed up-regulation of murine double minute 2 (MDM2), strictly p53-dependent, and detected an increase in expression of pro-apoptotic caspase 3 and BCL2-associated X (BAX) genes in both breast cancer cell lines expressing wild-type and mutant p53. In summary, the results suggest that our compounds promote apoptosis of breast cancer cell lines via p53-dependent and -independent pathways.

Keywords: MDM2; Spiro-bisheterocycles; apoptosis; breast cancer; cell proliferation; oxygen and nitrogen heterocycles; p53.