Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma

Abstract

Sorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-β1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.