Student University at Buffalo, New York, United States
Background: Ototoxicity is among the most debilitating adverse events associated with cisplatin, however contributing factors are not well understood and there are no known clinical interventions. A previous genome-wide association study identified MCT6 as a potential regulator of cisplatin ototoxicity (Drogemoller JAMA Oncol 2017), although confirmation and mechanistic insight into how the solute carrier promotes this adverse remains elusive. We hypothesize that a N-acetylcysteine S-conjugate metabolite of cisplatin (NAC-1) is an ototoxic molecule that accumulates intracellularly through MCT6. Methods: Cisplatin or NAC-1 (10 μM) uptake was assessed in OAT1 or MCT6 overexpressing Xenopus laevis oocytes and mock transfected cells for 1 hour at 37°C. Platinum concentration was measured using inductively coupled plasma mass spectrometry. Cochlear sensitivity to cisplatin or NAC-1 (0 – 100 μM) was measured in differentiated UBOC2 cells by evaluating cell viability with the Cell Titer-Glo Luminescent assay after 72 hours. Results: Cisplatin uptake into MCT6 or OAT1 overexpressing oocytes was not different from control cells (P = 0.52), however NAC-1 accumulation was increased 3.4 – and 1.5 – fold in MCT6 and OAT1 overexpressing oocytes, respectively, compared to control cells (P < 0.01). Differentiated UBOC2 cells demonstrated sensitivity to cisplatin with a half maximal effective concentration (EC50) of 24.3 μM (SD = 3.0). The EC50 of NAC-1 in UBOC2 cells was 29.1 μM (SD = 2.3). Conclusion: We report for the first time that NAC-1 cellular accumulation is increased in the presence of MCT6 and that differentiated cochlear cells are similarly sensitive to cisplatin and NAC-1 cytotoxicity. These findings support a role of NAC-1 in contributing to cisplatin-induced ototoxicity.
Drogemoller, B.I. et al. Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer. JAMA Oncol. Nov 1;3(11):1558-1562 (2017).
