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

The Authors thank the Unite de Nutition Humaine UMR 1019 INRA-UdA - Equipe ECREIN (France) and the University of Aveiro, Fundacao para a Ciencia e a Tecnologia (Portugal), EU, QREN, FEDER, COMPETE, for funding this biological and organic chemistry research. They also thank Algeria's General Directorate for Scientific Research and Technological Development (DGRSDT) for financial supportBreast 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 pathway