Polymorphic renal transporters and cisplatin’s toxicity in urinary bladder cancer patients: current perspectives and future directions

Abstract

Urinary bladder cancer (UBC) holds a potentially profound social burden and affects over 573,278 new cases annually. The disease’s primary risk factors include occupational tobacco smoke exposure and inherited genetic susceptibility. Over the past 30 years, a number of treatment modalities have emerged, including cisplatin, a platinum molecule that has demonstrated effectiveness against UBC. Nevertheless, it has severe dose-limiting side effects, such as nephrotoxicity, among others. Since intracellular accumulation of platinum anticancer drugs is necessary for cytotoxicity, decreased uptake or enhanced efflux are the root causes of platinum resistance and response failure. Evidence suggests that genetic variations in any transporter involved in the entry or efflux of platinum drugs alter their kinetics and, to a significant extent, determine patients’ responses to them. This review aims to consolidate and describe the major transporters and their polymorphic variants in relation to cisplatin-induced toxicities and resistance in UBC patients. We concluded that the efflux transporters ABCB1, ABCC2, SLC25A21, ATP7A, and the uptake transporter OCT2, as well as the organic anion uptake transporters OAT1 and OAT2, are linked to cisplatin accumulation, toxicity, and resistance in urinary bladder cancer patients. While suppressing the CTR1 gene’s expression reduced cisplatin-induced nephrotoxicity and ototoxicity, inhibiting the expression of the MATE1 and MATE2-K genes has been shown to increase cisplatin’s nephrotoxicity and resistance. The roles of ABCC5, ABCA8, ABCC10, ABCB10, ABCG1, ATP7B, ABCG2, and mitochondrial SLC25A10 in platinum-receiving urinary bladder cancer patients should be the subject of further investigation.

Cancer drugs and acute kidney injury: new therapies and new challenges

“…Unbound cisplatin is freely filtered through the glomeruli and then re-absorbed through the proximal tubules, mainly by OCT2 and CTR1 [12,13]. Cisplatin efflux mechanisms include mostly MATE-1 and ABCC2 [14]. Cisplatin nephrotoxicity is caused by inhibition of DNA repair and oxidative stress, a direct result of its antineoplastic properties effecting the renal proximal tubular cells, combined with the fact that the concentration of cisplatin in the kidney is about five times greater than its concentration in other tissues [15,16].…”

Development of a novel treatment based on PKMYT1 inhibition for cisplatin-resistant bladder cancer with miR-424-5p-dependent cyclin E1 amplification

“…Patients with advanced BC are treated with cisplatin combination chemotherapy [2]. Brie y, cisplatin attaches to the genomic or mitochondrial DNA and creates covalent adducts with them to induce DNA lesions; prevent the production of DNA, mRNA, and proteins; and halt DNA replication, all of which eventually lead to necrosis or death [4]. In addition, cisplatin induces apoptosis mediated by the activation of various signaling pathways, including calcium signaling, death receptor signaling, and activation of mitochondrial pathways [5].…”