Organic Cation Transporter 2 Mediates Cisplatin-Induced Oto- and Nephrotoxicity and Is a Target for Protective Interventions

The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wild-type and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies.¹ When combined with bleomycin and etoposide, cisplatin is considered to be curative treatment for testicular cancer.² However, the chemotherapeutic use of cisplatin is limited by serious side effects, such as nephrotoxicity and ototoxicity, sometimes requiring a reduction in dose or discontinuation of treatment. Even though nephrotoxicity can be managed with some success by concomitant use of i.v. hydration, it is still a major factor that limits the administration and efficacy of cisplatin in cancer therapy.³ Ototoxicity remains an unresolved clinical problem, especially in infants and younger children, where it leads to a considerable risk of delayed language development because of impaired perception of higher frequency consonant sounds that is of great importance in the presence of background noise. This may have devastating consequences for a young child''s social and educational development.⁴The molecular mechanisms of cellular cisplatin toxicity have been investigated intensively.² The ototoxic effects of cisplatin include loss of outer hair cells, blebbing of outer and inner hair cells, degeneration of the stria vascularis, and a decrease in the number of spiral ganglion cells.⁵ In the kidney, cisplatin highly accumulates in cells of the terminal proximal tubule and of the distal nephron, where it causes either apoptosis or necrosis, depending on exposure time and concentration.² Recently, some attention has been paid to the role of specific cellular uptake processes in cisplatin toxicity. The copper transporter (Ctr)1 seems to be involved in cisplatin accumulation in tumor cells⁶ as well as in the renal epithelial cells.⁷ However, the cisplatin uptake into renal tubular cells is also mediated by organic cation transporter (OCT)2 and the function of OCT2 is critically involved in the development of toxicity.^8,9 In humans, OCT2 (hOCT2) is highly expressed at the basolateral side of all three segments of the proximal tubule.¹⁰ It represents a subtype of three OCTs that belong to the SLC22 transporter family. OCTs are highly expressed in intestine, liver, and/or kidney and play a pivotal role in drug absorption and excretion.¹¹ They are polyspecific, electrogenic uniporters that may operate in both directions. Because the membrane potential provides part of the driving force, they preferably mediate organic cation uptake into cells at normal membrane potential.¹² OCT2 has been proposed as target for protective therapeutic interventions accompanying cisplatin treatment. In vitro studies showed that administration of cisplatin together with a second substrate of organic cation transporters decreases cellular cisplatin accumulation protecting renal cells from cisplatin toxicity.^8,9In the present study, we demonstrated in an in vivo model that OCT2 plays a pivotal role in the development of cisplatin induced oto- and nephrotoxicity. For the first time we showed that cisplatin ototoxicity is linked to the expression of OCT2 in hair cells of the cochlea. Furthermore, the feasibility of a therapeutic approach aimed to reduce cisplatin toxicities has been demonstrated in vivo. These findings are very important to establish chemotherapeutic protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.