Clomipramine potentiates sorafenib efficacy in rat HCC via lysosomal sequestration and cathepsin B/Bcl-2/Beclin-1.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, often diagnosed late, necessitating systemic chemotherapy. A major challenge in HCC treatment is chemoresistance, often driven by lysosomal sequestration of drugs like sorafenib (SB), which reduces effective drug concentrations at target sites. Additionally, autophagy activation can contribute to resistance. This study investigates combining SB with the lysosomotropic drug clomipramine (CM) to enhance chemosensitivity by overcoming lysosomal sequestration and modulating autophagy-related pathways.

Researchers induced experimental Hepatocellular Carcinoma (HCC) in 48 healthy Wistar albino male rats using intraperitoneal diethylnitrosamine (DENA) (200 mg/kg), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. After HCC induction, rats were divided into groups: control, Sorafenib (SB) (10 mg/kg orally daily × 21 days), Clomipramine (CM) (10 mg/kg orally daily × 21 days), and a combination group receiving both SB and CM (10 mg/kg each orally daily × 21 days). Primary endpoints included neoplastic features, hepatic Bcl2 and Beclin-1 expression, and cytosolic cathepsin B release, assessed alongside transmission electron microscopy (TEM) for autophagosome accumulation.

The combination of Clomipramine (CM) and Sorafenib (SB) significantly decreased neoplastic features in the HCC group compared to monotherapy.

Specifically, the combination treatment led to a decrease in hepatic Bcl2 expression and an increase in the release of cytosolic cathepsin B. Furthermore, hepatic Beclin-1 concentration was reduced in the combination group. Transmission electron microscopy (TEM) revealed autophagosome accumulation in the combination group, suggesting modulation of autophagy. These findings collectively indicate that the synergistic action of CM and SB targets the cathepsin B/Bcl2/Beclin-1 pathway, overcoming mechanisms of chemoresistance. The study highlights a novel approach to enhance the efficacy of sorafenib in HCC, potentially by disrupting lysosomal drug sequestration and modulating key apoptotic and autophagic pathways.