Deoxypodophyllotoxin, a semi-synthetic compound from Dysosma versipellis, induces selective cell death in human breast cancer cell lines

Biologically active compounds isolated from medicinal herbs have been the center of interest for researchers to investigate their possible effects and mechanisms through which they exert their action. In the current study, we investigated the antiproliferative effect and the mechanism of action of deoxypodophyllotoxin, a semi-synthetic compound derived from the extract of a Chinese herbal medicine, Dysosma versipellis (Hance) M. Cheng ex Ying (Berberidaceae). The study was conducted on MCF-7 and MDA-MB-231 breast cancer cell lines. The antiproliferative effect of deoxypodophyllotoxin was assessed by the Cell Counting Kit-8 assay. Flow cytometry, Annexin V/PI, mitochondrial membrane potential, caspase inhibition assays, and western blot analysis were performed to detect, explore, and assess the antiproliferative effect of deoxypodophyllotoxin. Our data revealed that, deoxypodophyllotoxin treatment resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 cell growth with very low IC50 (10.91 and 20.02 nM, respectively). It disrupted the cytoskeleton and induced significant cell cycle arrest at the G2/M phase in both cell lines through the interference with cell cycle regulatory proteins: cyclin B1, cdc25c, and CDK1. In MCF-7 cells, cell cycle inhibition was associated with apoptosis, which was caspase-dependent and involved elevation of Bax protein and a cleavage of PARP, this finding along with disruption of mitochondrial membrane potential, confirmed the involvement of intrinsic pathway in deoxypodophyllotoxin-induced apoptosis in MCF-7 cells. However, in MDA-MB-231 cells, deoxypodophyllotoxin is cytostatic and significantly suppresses proliferation by cell cycle arrest at G2/M phase without apoptotic induction. Such an activity of deoxypodophyllotoxin could be expected to spare normal tissues from toxic side effects.