Renal protection by 3H-1,2-dithiole-3-thione against cisplatin through the Nrf2-antioxidant pathway

Cisplatin is commonly used for the treatment of several solid tumors. However, its clinical use is often limited by renal toxicity. The indirect antioxidant 3H-1,2-dithiole-3-thione (D3T) has been known to protect cells from oxidative damage by up-regulating the expression of antioxidative genes through the transcription factor NF-E2-related factor 2 (Nrf2) pathway. We hypothesized that D3T treatment may be protective against cisplatin-induced nephrotoxicity by enhancing the antioxidative capacity of renal cells. In cultured murine tubular epithelial cells, D3T facilitates the nuclear accumulation of Nrf2 and the subsequent expression of its target genes such as glutamate cysteine ligase (GCL). Increased GSH pool in D3T-treated renal cells appears to be associated with amelioration of cisplatin-mediated cell death. Protective effects of D3T were also observed in mice. Oral administration of D3T (0.25 mmol/kg) increased the expression of GCL in mouse kidney, which resulted in suppression of cisplatin-mediated increases in blood urea nitrogen and serum creatinine. Histopathological changes representing cisplatin-induced acute renal failure were also effectively ameliorated by D3T treatment. Collectively, these results indicate that pharmacological activation of the Nrf2 pathway might have a beneficial effect on reducing chemotherapy-associated cytotoxic adverse effects.