Carvacrol enhances anti-tumor activity and mitigates cardiotoxicity of sorafenib in thioacetamide-induced hepatocellular carcinoma model through inhibiting TRPM7

Aims: Sorafenib (Sora) represents one of the few effective drugs for the treatment of advanced hepatocellular carcinoma (HCC), while resistance and cardiotoxicity limit its therapeutic efficacy. This study investigated the effect of transient receptor potential melastatin 7 (TRPM7) inhibitor, carvacrol (CARV), on overcoming Sora resistance and cardiotoxicity in thioacetamide (TAA) induced HCC in rats. Materials and methods: TAA (200 mg/kg/twice weekly, intraperitoneal) was administered for 16 weeks to induce HCC. Rats were treated with Sora (10 mg/Kg/day; orally) and CARV (15 mg/kg/day; orally) alone or in com-bination, for six weeks after HCC induction. Liver and heart functions, antioxidant capacity, and histopathology were performed. Apoptosis, proliferation, angiogenesis, metastasis, and drug resistance were assessed by quantitative real time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry.Key findings: CARV/Sora combination significantly improved survival rate, and liver functions, reduced Alpha-Fetoprotein level, and attenuated HCC progression compared with Sora group. CARV coadministration almost obviated Sora-induced changes in cardiac and hepatic tissues. The CARV/Sora combination suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, NOTCH1, Spalt like transcription factor 4, and CD133. CARV boosted Sora antiproliferative and apoptotic activities by decreasing cyclin D1 and B-cell leukemia/lymphoma 2 and increasing BCL2-Associated X and caspase-3. Significance: CARV/Sora is a promising combination for tumor suppression and overcoming Sora resistance and cardiotoxicity in HCC by modulating TRPM7. To our best knowledge, this study represents the first study to investigate the efficiency of CARV/ Sora on the HCC rat model. Moreover, no previous studies have reported the effect of inhibiting TRPM7 on HCC.