P0026 Novel quinuclidinone derivative induced apoptosis in human MCF-7 breast cancer cells by targeting p53

Abstract

Background Identification of agents that are non-toxic but that can delay onset and/or progression of breast cancer is highly desirable. Methods In this study, novel quinuclidinone derivatives have been synthesised to investigate their impact on human MCF-7 breast cancer cell lines and MCF-12a normal breast epithelial cells after an initial screening study. Findings We identified a novel derivative that induced apoptosis in MCF-7 cells more than in MCF-12a, which was further confirmed by TUNEL assay. Our novel quinuclidinone derivative abrogated G 2 /M checkpoint as confirmed by the increased expression levels of cyclin B and reduction of cyclin D levels. It reduced expression levels of survival proteins Mdm2, Akt, and ERK1/2 and increased expression levels of Bad and PUMA. Furthermore, it increased expression of p53 and its translocation from cytoplasm to nucleus, and also significantly increased Bax expression at both the mRNA level and protein level. Moreover, the apoptosis induction by our derivative was inhibited by the p53 inhibitor PFT- α , as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both quinuclidinone derivative and PFT- α . Our molecular docking experiments revealed a docked pose of quinuclidinone derivative bound to p53 regulatory domain using the Molecular Operating Environment module. Our in vivo studies in a breast cancer animal model showed that our novel derivative significantly reduced tumour volumes after 6 weeks and significantly improved physiological processes. Interpretation Together, the results of the present study show that our novel quinuclidinone derivative provokes apoptosis in human breast cancer cells (MCF-7) by targeting p53 signalling without any apparent toxicity in rats.