Cisplatin : an old drug with a newfound efficacy -- from mechanisms of action to cytotoxicity.

INTRODUCTION: Cisplatin is a highly effective antineoplastic drug with an extremely current mechanism of action. Cisplatin-induced side effects are dose-dependent and limit the administration of increased dosages, thus compromising its therapeutic efficacy. AREAS COVERED: This review aims to describe the emerging knowledge about the biochemical mechanisms that mediate cisplatin cytotoxicity and side effects. A specific section is devoted to discuss the pathogenesis of cisplatin-related toxicities and the potential measures to counteract them. EXPERT OPINION: Although cisplatin has been used for a long time, only recently its exact mechanism of action has been better defined. The cytotoxic activity of cisplatin is largely dependent on the glycolytic metabolism of tumor cells: cisplatin redirects cancer cells to oxidative phosphorylation from the 'Warburg effect', which is considered one of the most important mechanisms of tumor cell survival. The interference of cisplatin with glucose metabolism is also a cause of its relevant toxicities. The emerging knowledge on the complex mechanisms, which mediate cisplatin cytotoxicity and side effect, may lead to a more appropriate and safe use of this drug. Further studies are warranted to define and implement its effectiveness in combination with targeted drugs able to interfere with cellular energy metabolism, such as mTOR inhibitors.