The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells

Although the redox-active synthetic isoflavene, phenoxodiol, is in Phase 3 clinical trials for drug-resistant ovarian cancer, and in early stage clinical trials for prostate and cervical cancer, its primary molecular target is unknown. Nevertheless, phenoxodiol inhibits proliferation of many cancer cell lines and induces apoptosis by disrupting FLICE-inhibitory protein, FLIP, expression and by caspase-dependent and -independent degradation of the X-linked inhibitor of apoptosis, XIAP. In addition, phenoxodiol sensitizes drug-resistant tumour cells to anticancer drugs including paclitaxel, carboplatin and gemcitabine. Here, we investigate the effects of phenoxodiol on plasma membrane electron transport (PMET) and cell proliferation in human leukemic HL60 cells and mitochondrial gene knockout HL60ρo cells that exhibit elevated PMET. Phenoxodiol inhibited PMET by both HL60 (IC50 32 μM) and HL60ρo (IC50 70 μM) cells, and this was associated with inhibition of cell proliferation (IC50 of 2.8 and 6.7 μM, respectively), pan-caspase activation and apoptosis. Unexpectedly, phenoxodiol also inhibited PMET by activated murine splenic T cells (IC50 of 29 μM) as well as T cell proliferation (IC50 of 2.5 μM). In contrast, proliferation of WI-38 cells and HUVECs was only weakly affected by phenoxodiol. These results indicate that PMET may be a primary target for phenoxodiol in tumour cells and in activated T cells.