Catanzaro Daniela, Nicolosi Silvia, Cocetta Veronica, Salvalaio Marika, Pagetta Andrea, Ragazzi Eugenio, Montopoli Monica, Pasut Gianfranco
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
Venetian Institute of Molecular Medicine, Padova, Italy.
Oncotarget. 2018 Mar 30;9(24):16847-16860. doi: 10.18632/oncotarget.24708.
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.
卵巢癌是一种侵袭性和致命性癌症，通常采用细胞减灭术，随后进行化疗。不幸的是，在初始缓解后，许多患者会复发，主要原因是对标准化疗方案（卡铂/紫杉醇）产生耐药性，而且该方案还受到严重副作用的影响。为了解决这些问题，本文研究了脂质体顺铂与6-氨基烟酰胺的联合应用。已知耐药细胞对葡萄糖的需求增加，其中部分葡萄糖被重新导向磷酸戊糖途径（PPP）。有趣的是，我们发现卵巢癌细胞系IGROV1的顺铂耐药亚克隆也将其代谢转向糖酵解途径，并依赖PPP来逃避顺铂的细胞毒性。药物6-氨基烟酰胺是葡萄糖-6-磷酸脱氢酶（PPP的限速步骤）的抑制剂，可恢复耐药细胞对顺铂的敏感性。然后，为了降低顺铂的毒性并延长其作用时间，开发了一种冻干的隐形脂质体顺铂制剂。脂质体顺铂与6-氨基烟酰胺的联合治疗在耐药细胞中显示出有前景的细胞毒性活性，并且在大鼠体内具有延长的药代动力学，从而为卵巢癌的新治疗选择开辟了道路。
