BIOCHEMICAL AND MOLECULAR MECHANISMS OF ACTION OF CISPLATIN IN CANCER CELLS

Cisplatin (cis-Diamminedichloroplatinum II) is one of the most important chemotherapeutic agents widely used in treatment of many types of solid cancer. Accumulating evidence suggests that the cytotoxic activity of cisplatin involves both nuclear and cytoplasm component, but its biochemical and molecular mechanisms of action are still unclear. Its mode of action is linked to the ability of cisplatin to interact with purine bases on the DNA, causing DNA damage, interfering with DNA repair mechanisms and inducing apoptotic cell death in cancer cells. The major limitations in the clinical application of cisplatin are the numerous side effects and the development of cisplatin resistance by tumors. Mechanisms that can explain cisplatin resistance include the reduction in drug accumulation inside the cell, higher concentration of glutathione and metallothioneins, faster repair of cisplatin adducts and modulation of apoptotic cell death in various cells. In this article we review the pathways that cisplatin can activate in cancer cell, the mechanisms of resistance and clinical toxicities. A deep knowledge of mechanisms of action may lead to design of more efficient platinum-based antitumor drugs and provide new therapeutic strategies in cancer treatment