Multiple targets modulation of Bcl-2/CD1, caspase-3 and refinement of AKT/ERK signalling by sorafenib in hepatocellular carcinoma in rats; comprehensive outlook

Abstract

Background Hepatocellular carcinoma (HCC) is the commonly diagnosed cancer among the three top ranked cancer induced mortality in cancer patients worldwide. A tyrosine kinase inhibitor sorafenib has been used as systemic therapy with a demonstrated survival benefit in HCC. Objectives The present work was conducted to investigate the multiple targets that may be involved in the action of sorafenib in treatment of HCC and development of drug resistance. Materials and methods Four groups of Swiss albino rats were assigned for 12 weeks treatment as the following: group (I) untreated control, group (II): rats received Diethyl Nitrosamine(DEN) (200 mg/kg, i.p)+Carbon Tetra Chloride (CCl4)(3 ml/kg, sc) every week for the first eight weeks, group (III): daily treatment with sorafenib (10 mg/kg, p.o.) for last 4 weeks, group (IV) sorafenib treatment after DEN + CCl4 treatment. Blood samples, and liver tissues were removed for collection to perform biochemical analysis (alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alpha fetoprotein (AFP), B-cell lymphoma 2 (Bcl-2), cyclin D1 (CD1), nuclear factor kappa light chain enhancer of activated B cells (NF-kB), caspase-3, and gene expression of AKT, and ERK 1/2, as well as histological examinations. Results and conclusion Administration of diethyl nitrosamine and carbon tetra chloride showed severe changes in all measured parameters and histological photomicrographs. Daily treatment with sorafenib markedly decreased B-cell lymphoma 2 (Bcl-2), cyclin D1 (CD1), nuclear factor kappa light chain enhancer of activated B cells (NF-kB) accompanied by improvement of active caspase-3. Sorafenib succeeded in restoring the gene expression of ERK 1/2 and AKT level and refinement of histological patterns in animals induced with DEN and CCL4. Sorafenib interrupts various cell communication pathways that control cancer progression, angiogenesis, and cell survival. Sorafenib regulates the AKT/ERK signaling pathway in HCC. study highlights the importance of investigating other therapeutic targets that may help combat sorafenib resistance in relation to different DNA repair mechanisms.