Cisplatin as a Xenobiotic Agent: Molecular Mechanisms of Actions and Clinical Applications in Oncology
Monia Cecati, Valentina Pozzi, Veronica Pompei, Valentina Schiavoni, Stefania Fumarola, Alice Romagnoli, Giovanni Tossetta, Angelo Montana, A. Polizzi, Davide Sartini, Roberto Campagna
Abstract
Cisplatin, a platinum-based compound, is a cornerstone of modern chemotherapy and remains widely used against a variety of solid tumors, including testicular, ovarian, lung, bladder, and head and neck cancers. Its anticancer activity is primarily attributed to the formation of DNA crosslinks, which obstruct replication and repair, ultimately leading to apoptosis. However, the clinical value of cisplatin is constrained by two major challenges: its toxic profile and the development of resistance. Cisplatin toxicity arises from its interaction not only with tumor DNA but also with proteins and nucleic acids in healthy tissues, resulting in a range of adverse effects, including, but not limited to, nephrotoxicity, ototoxicity, neurotoxicity, and gastrointestinal injury. In pediatric patients, permanent hearing loss represents a particularly debilitating complication. On the other hand, tumor cells can evade cisplatin cytotoxicity through diverse mechanisms, including reduced intracellular drug accumulation, enhanced DNA repair, detoxification by thiol-containing molecules, and alterations in apoptotic signaling. These resistance pathways severely compromise treatment outcomes and often necessitate alternative or combination strategies. This review examines the chemical structure of cisplatin, the molecular mechanisms of cisplatin cytotoxicity and cisplatin-induced resistance, as well as the main applications in cancer management and the complications associated with its clinical use.