Membrane transporters as mediators of cisplatin side-effects

Abstract

The clinical use of the efficient chemotherapeutic drug cisplatin is limited by its specific severe organ toxicities such as nephro-, oto-, and also peripheral neurotoxicity. Membrane transporters such as the copper transporter-1 (Ctr1), the copper transporter-2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter-2 (OCT2), and the multidrug extrusion transporter-1 (MATE1) mediate cellular transport of cisplatin. Since OCT2 is specifically expressed in the kidneys, its role as possible target of specific organ protection against undesired cisplatin toxicity is under investigation. We could show that OCT2 is also expressed in the cochlea in hair cells and in cells of the stria vascularis and also in dorsal root ganglia of mice. Moreover, we could show in a mouse model of cisplatin acute toxicities that the expression of OCT is critical for the development of ototoxicity, peripheral neurotoxicity and nephrotoxicity. Competition of cisplatin transport by the OCT2 substrate cimetidine was able to suppress ototoxicity, and reduce nephrotoxicity. Only few human tumors express OCT2, its expression being apparently down-regulated by epigenetic modifications, suggesting that a protective therapy by competition for the transport of cisplatin by OCT2 may be generally feasible without affecting its antitumor potency. There is already some evidence that patients bearing a mutation in OCT2 gene or co-medicated with cimetidine are protected against cisplatin nephrotoxicity. In conclusion, OCT2 seems to be an ideal target for the establishment of protective therapies aimed to specifically reduce cisplatin side-effects and increase the quality of life of the patients.