Cisplatin liposome and 6-amino nicotinamide combination to overcome drug resistance in ovarian cancer cells

Abstract

Ovarian cancer is an aggressive and lethal cancer usually treated by cytoreductive surgery followed by chemotherapy. Unfortunately, after an initial response, many patients relapse owing mainly to the development of resistance against the standard chemotherapy regime, carboplatin/paclitaxel, which is also affected by heavy side effects. In view to addressing such issues here, an association of liposomal cisplatin with 6-amino nicotinamide is investigated. It is known that resistant cells increase their demand for glucose, which is partially redirected toward the pentose phosphate pathway (PPP). Interestingly, we have found that also a cisplatin-resistant subclone of the ovarian cancer cells IGROV1 switch their metabolism toward the glycolytic pathway and rely on PPP to elude cisplatin cytotoxicity. The drug 6-amino nicotinamide, an inhibitor of the enzyme glucose-6-phosphate dehydrogenase (the rate-limiting step of the PPP) can restore the sensitivity of resistant cells to cisplatin. Then, to reduce the toxicity of cisplatin and prolong its action, a lyophilized stealth liposomal formulation of cisplatin was developed. The combination treatment of liposomal cisplatin and 6-amino nicotinamide showed promising cytotoxic activities in drug-resistant cells and a prolonged pharmacokinetics in rats, thus opening the way for a new therapeutic option against ovarian cancer.