Modulation Of Resistance To Sorafenib In Human Hepatocellular Carcinoma Cell Line(s) Using Phytochemical(s)

Abstract

Hepatocellular carcinoma is the major type of primary liver malignancy with high rates of mortality worldwide. Hepatocellular carcinoma tumors have poor prognosis and are usually diagnosed at late stages when potentially curative therapeutic interventions become inapplicable. Most HCC tumors are inherently resistant to chemotherapy and despite the tremendous advances in cancer chemotherapy, their treatment remains quite challenging. Recently, targeted therapy gained considerable attention in cancer chemotherapy in order to achieve specificity towards cancer cells and to limit toxicities. This opened the door for tyrosine kinase inhibitors as potentially curative chemotherapeutic agents. Sorafenib is an orally active multikinase inhibitor with multiple anti-angiogenic and apoptotic activities. Since 2008, sorafenib became the first and only pharmacological agent clinically approved for the treatment of advanced HCC. However, despite the success achieved by sorafenib in clinical trials, overall survival was limited suggesting the presence of MDR mechanisms. Thus, the search for new agents acting in synergy with sorafenib became highly essential. Lately, natural compounds including dietary phytochemicals have demonstrated promising chemopreventive potentials in many cancers including HCC. Among these promising phytochemicals is I3C. Indole-3-carbinol was extensively studied for its selective cytotoxic potentials towards cancer cells as well as its abilities to chemosensitize several cancer cell lines to chemotherapeutic agents. Accordingly, the current study was conducted to investigate the potential chemosensitizing effects of the phytochemical, I3C, on sorafenib cytotoxicity in HCC cell line, HepG2. Also, the putative mechanisms underlying this modulation were explored in terms of their effects on apoptotic and angiogenic machineries as well as on tumor invasiveness. Light was shed on the Summary and Conclusions 149 contribution of NOX-1, a member of the NOX family of enzymes, in I3C modulatory effects as well as on clusterin which has been reported to be involved in HCC metastasis, chemoresistance and apoptosis. To fulfill these