Cisplatin is one of the most widely used anticancer agents, including for the treatment of solid tumors in children and adults. The clinical use of cisplatin is associated with dose-limiting damage to renal tubular cells (nephrotoxicity), which occurs in up to 40% of patients despite intensive prophylactic measures, as well as with toxicity to cochlea (ototoxicity) and peripheral nerves (neurotoxicity), and these complications may limit further treatment or even threaten life. There is currently no known specific treatment for cisplatin-induced toxicities, and mechanistic details of these side effects remain poorly understood. We have recently found that the ability of platinum chemotherapeutics to cause damage to healthy tissues cells is dependent on organic cation transporters (OCT) and, for renal tubular cells, organic anion transporters (OAT) as well. In mice, these processes were found to be regulated by the two pairs of closely related transporters, Oct1/Oct2 that regulate cellular uptake of cisplatin, and Oat1/Oat3 that regulate renal uptake of a cisplatin mercapturic acid metabolite that acts as a precursor of a potent nephrotoxin. We found that the function of these 4 transporters can be potently inhibited by the tyrosine kinase inhibitor nilotinib, through non-competitive mechanisms. In the current proposal, we outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT and OAT function with nilotinib will specifically affect accumulation of cisplatin in healthy target tissues and affect its downstream toxic effects: (i) Using various in vitro and in vivo models, including zebrafish and mice, we will further determine the qualitative and quantitative effects of nilotinib on the function of Oct1/Oct2 and Oat1/Oat3; (ii) Studies in zebrafish and mice with or without specific transporters and kinases of interest will determine the direct contribution of these proteins to cisplatin-related toxicity, including nephrotoxicity, ototoxicity, and neurotoxicity, as well as drug disposition properties and drug- drug interaction potentials; (iii) Using mice with or without human tumor xenografts derived from replicating cell lines or patient tumors, we will determine the direct contribution of these proteins to cisplatin-related anticancer efficacy, and the in vivo effects of nilotinib on this phenotype. The demonstration of reduced cisplatin-induced toxicity through inhibition of critical transporters regulating access of the drug to healthy tissues will provide the foundation for additional studies in the future aimed at ameliorating this agent's debilitating side effects in routine clinical practice.
Cisplatin is among the most effective and widely prescribed anticancer agents but its clinical use is associated with dose-limiting, irreversible kidney damage (nephrotoxicity), and to a lesser extent, hearing loss (ototoxicity) and damage to peripheral nerves (neurotoxicity). Using unique genetic mouse models, we found that cisplatin nephrotoxicity, ototoxicity, and neurotoxicity are dependent on transporter-mediated drug uptake. Our proposed studies are of direct human relevance because targeted interference of the identified transport systems with small-molecule xenobiotics may mitigate the incidence and severity of these debilitating side effects in humans.
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