review · Medical Oncology
Urinary bladder cancer causes a substantial disease burden worldwide, with cisplatin serving as an effective treatment modality despite severe dose-limiting toxicities such as kidney damage. Cisplatin requires intracellular accumulation to destroy cancer cells, meaning drug resistance and treatment failure stem from altered uptake or enhanced efflux. Inherited genetic variations in cellular drug transporters influence these drug kinetics and shape individual patient responses. Multiple transporters, including ABCB1, ABCC2, SLC25A21, ATP7A, OCT2, OAT1, and OAT2, relate directly to cisplatin accumulation, side effects, and resistance. Furthermore, suppressing the expression of CTR1 decreases cisplatin-induced kidney and hearing damage, whereas inhibiting MATE1 and MATE2-K worsens kidney toxicity and drug resistance. Several additional transporters, including ABCC5, ABCA8, ABCC10, and mitochondrial SLC25A10, require further study to establish their full impact on therapy.
Cisplatin is a key chemotherapy for bladder cancer, but kidney damage often restricts the doses patients can safely receive. By identifying the specific genetic variations in cellular transporters that drive toxicity and treatment resistance, medical researchers can better understand why individuals respond differently to therapy and how to design strategies that safeguard vital organs without reducing anti-cancer effects.
This research provides early-stage biological insights that could inform the future design of genetic screening panels or targeted adjuvant therapies aimed at reducing chemotherapy side effects. Potential end users include diagnostic developers and pharmaceutical researchers working on personalised oncology. The work represents foundational review-level evidence and remains at an early, pre-clinical stage far from direct commercial deployment.
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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.
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DOI: 10.1007/s12032-022-01928-0
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