Clomipramine potentiates sorafenib efficacy in experimental hepatocellular carcinoma by targeting lysosomal sequestration and modulating the cathepsin B/Bcl-2/Beclin-1 axis

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common causes of death around the world, and it is commonly diagnosed late, so systemic chemotherapy is commonly used. Lysosomal sequestration of chemotherapy drugs such as sorafenib [1] decreases the effective concentration of chemotherapy at the target sites and leads to chemoresistance, also chemoresistance may arise from autophagy activation. We aimed to find a new therapeutic regimen for HCC through enhancing the chemosensitivity of SB by combining it with the lysosomotropic drug clomipramine (CM). METHODS AND RESULTS: 48 healthy Wister albino male rats were included. Induction of experimental HCC was done by intraperitoneal injection of diethylnitrosamine (DENA) (200 mg/ kg), after that, phenobarbital sodium (0.05%) was added to drinking water for 18 weeks. After induction, SB (10 mg/kg) was taken orally for 21 days. CM (10 mg/kg) was also provided orally for 21 days. The combination group received SB and CM (10 mg/kg) for 21 days. CONCLUSION: Treatment by CM in combination with SB could decrease neoplastic features in HCC group. The hepatic expression of Bcl2 was decreased, and the release of cytosolic cathepsin B was increased in the combination group. Also, the hepatic concentration of Beclin-1 decreased in the combination group and there was autophagosome accumulation in transmission electron microscope (TEM). The results indicate that the concomitant use of CM and SB may be considered a possible new therapeutic option in managing HCC by targeting the cathepsin B/Bcl2/Beclin-1 pathway.