Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

Abstract

Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients' responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

Keywords: chemotherapy; cisplatin; molecular mechanisms; resistance.

Figure 1

The behaviour of cisplatin in aqueous solution. Cisplatin (1) is a bright-yellow solid; when dissolved in water it is attacked by water molecules and as a result one of the chloride ions is eliminated and monoaqua (2) species is formed. Diaqua species (3) is formed when the second water molecule replaces the chloride ion. Water replaces chloride ions because the metal and nitrogen form stronger bond than metal and the chloride ion. Bound water became very acidic and at physiologic pH became completely deprotonated – as a monohydroxo form (4), and the product of the dissociation of the second proton from the diaqua form is dihydroxo species (6). Logarithms of rate constants (pK₁, pK_-1, pK₂ and pK_-2) are given for 25 ºC and of dissociation constants (pK_a1, pK_a2 and pK_a3) for 27 ºC.

Figure 2

Traffic of cisplatin (CP). 1, passive diffusion, 2, passive diffusion blocked. See text for explanations. CP: cisplatin, DACP: diaqua cisplatin, OCT: organic cation transporter, OAT: organic anion transporter, Ctr: copper transporter, MRP: multidrug resistance-associated protein, ATP7: copper-transporting P-type ATPase, MATE: multidrug extrusion transporter, GSH: glutathione, MT: metallothionein.