Membrane transporters as mediators of toxicities induced by chemotherapeutic agents

• Applicant: Professor Dr. Giuliano Ciarimboli
• Subject Area: Anatomy and Physiology ; Nephrology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389197969

Transporters are important mediators of specific cellular uptake and thus of the effects, side effects, metabolism and excretion of many important chemotherapeutic drugs, such as cisplatin. Cisplatin is a potent cytostatic drug which is considered to be curative against testicular cancer but whose use is limited by its severe acute and chronic nephro-, oto- and peripheral neurotoxicity. The expression of the organic cation transporter 2 (OCT2) in the structures which are damaged by cisplatin but are not target of the therapy, is positively associated with the development of both acute and chronic toxicity. On the other hand, expression of the Multidrug- and Toxin-Transporter 1 (MATE1) is negatively associated with cisplatin nephrotoxicity. In this project we want to investigate the molecular mechanisms of cisplatin toxicities and their dependence on transporters by performing a proteomic, phosphoproteomic, and degradomic analysis of the kidneys, peripheral nerves, cochlea, serum, and urine from WT and OCT knockout (KO) mice after acute or chronic treatment with cisplatin. Moreover, it will be investigated whether OCT2 and MATE1 are suitable targets of protective interventions aimed at reducing undesired side effects of chemotherapy with cisplatin in kidney, cochlea and neuronal cells. We will examine whether specific inhibition or regulation of these transporters is able to decrease cisplatin toxicities in vitro and in vivo. Finally, it will be examined in vivo whether these protective approaches protect against acute and chronic cisplatin toxicity without affecting its anti-tumoral efficacy.

• DFG Programme: Research Grants