Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition.

Abstract

The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.