CaV3.3 T-type calcium channels contribute to carboplatin resistance in retinoblastoma

Carboplatin resistance in retinoblastoma, an aggressive pediatric intraocular tumor, remains a major clinical challenge in treatment. This study elucidates the role of T-type calcium channels in carboplatin resistance using human retinoblastoma Y79 cells. We generated carboplatin-resistant Y79 (Y79CR) cells and characterized their electrophysiological properties. Patch-clamp recordings revealed a subpopulation of enlarged Y79CR cells (i.e., giant cells) with hyperpolarized resting membrane potentials, reduced input resistance, and increased T-type calcium currents. Quantitative RT-PCR analysis confirmed upregulation of Ca_V3.3 mRNA in Y79CR cells, identifying Ca_V3.3 as the predominant channel mediating these currents. Pharmacological inhibition of Ca_V3.3 using ML218 and TAT-C3P attenuated the sustained currents and partially restored carboplatin sensitivity, as evidenced by decreased IC₅₀ values in Y79CR cells. These findings demonstrate a critical role for T-type calcium channels, particularly Ca_V3.3, in mediating chemoresistance in retinoblastoma. Our results suggest that targeting these channels may provide a potential strategy to enhance the efficacy of carboplatin-based therapy in retinoblastoma treatment.