Saving ears and kidneys from cisplatin

Wensing K., Ciarimboli G.

Abstract

Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and also peripheral neuro-toxicity. Since transporters are important mediators of specific cellular uptake of many drugs such as cisplatin, their role as possible targets of specific organ protection against undesired cisplatin toxicities is under investigation. Several transporters are able to mediate the movement of cisplatin across the plasma membranes: Copper transporter-1 (Ctr1), copper transporter-2 (Ctr2), P-type copper-transporting ATPases ATP7A and ATP7B, organic cation transporter-2 (OCT2), and multidrug extrusion transporter-1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrates. In the present review article, we focus on the role of Ctr1 and OCT2 for cellular uptake of cisplatin and on the possibilities to reduce cisplatin-associated toxicities decreasing cisplatin uptake mediated by these transporters. The ubiquitously expressed Ctr1 seems to be involved in general cisplatin uptake in tumor and normal cells. Conversely, OCT2 expression is restricted to few cells such as renal, cochlear, and nervous cells, while its expression in some tumors seems to be epigenetically downregulated. For this reason, specific inhibition of OCT2 may be effective in decreasing cisplatin uptake in non-target cells, without compromising its anti-tumoral efficacy, and therefore OCT2 may be the target for a suitable protective therapy.