Identification of 7,8-Diacetoxy-3-Arylcoumarin Derivative as a Selective Cytotoxic and Apoptosis-inducing Agent in a Human Prostate Cancer Cell Line.

Coumarins are a member of the benzopyrone family of compounds with diverse and interesting pharmacological properties. In the present study, we report the in vitro cytotoxicity evaluation of 7,8-Diacetoxy-3-arylcoumarin derivatives (5a-h) in human prostate (PC-3) and breast (MDA-MB-231) cancer cell lines.

The cytotoxic activity was evaluated using crystal violet dye-binding assay. Furthermore, the most active compound in vitro cytotoxic activity in human non-cancerous cell line and its effect on the cell-cycle phases, apoptosis proteins expression, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and Glutathione (GSH) level were performed.

Among the eight compounds that were evaluated, 7,8-Diacetoxy-3-(4-methylsulfonyl phenyl)coumarin (5f) was the most active derivative with highest cytotoxic activity and selectivity against the PC-3 cell line vs. the non-cancerous WPE1-N22 cell line. The cytotoxic action of compound 5f in PC-3 cells is associated with the cell-cycle arrest at -G0/G1 phase, apoptosis, loss in mitochondrial membrane potential (MMP), induced reactive oxygen species (ROS) production and depletion of Glutathione (GSH) level.

The result indicates that the presence of p-methylsulfonylphenyl group on compound 5f is critical in modulating selective cytotoxic activity and induction of apoptosis via the mitochondrial apoptotic signaling pathway that is independent of cytochrome c release.