Hypercholesterolemia-induced impairment in sorafenib functionality is overcome by avasimibe co-treatment

Abstract

Avasimibe; a cholesterol-lowering drug with a proven safety in clinical trials, has recently been repositioned as an anticancer agent in various preclinical investigations. A study from our group reported that hypercholesterolemia promotes hepatocellular carcinoma (HCC) cell survival and hampers the anticancer effect of sorafenib, a kinase inhibitor. In the present study, we demonstrate that in HCC under hypercholesterolemic conditions the anticancer property of sorafenib is potentiated by avasimibe (AVA) co-treatment. Further, to elucidate the role of hypercholesterolemia on sorafenib efficacy, in vitro and in vivo models of HCC were used. In vitro, co-treatment of both drugs synergistically inhibited HCC cell viability and induced cell death under normal and hypercholesterolemic conditions. At the molecular level, downregulation of ERK signalling and induction of endoplasmic reticulum stress are likely to contribute to the combinatorial cytotoxic effect of sorafenib and avasimibe in vitro. In mice, fed on a high-cholesterol diet (HCD), the efficacy of sorafenib was restored by co-administration of AVA. Collectively, these findings suggest that impairment in the efficacy of sorafenib because of hypercholesterolemic phenotype could be restored by AVA co-treatment, which may have implications towards treatment strategy. HighlightsO_LICholesterol impedes sorafenib efficacy in Hepatocellular carcinoma cells. C_LIO_LIAvasimibe restores the functionality of sorafenib under hypercholesterolemic environment. C_LIO_LICombine treatment of sorafenib and avasimibe synergistically enhances cytotoxicity in hepatocellular carcinoma. C_LIO_LISorafenib and avasimibe treatment in the presence of LDLc.is associated with diminished ERK activation and increased ER stress. C_LI