Multimodality of human epidermal growth factor receptor-2 antagonism restores the apoptotic capacity of liver cancer cells

Abstract

Background: Hepatocellular carcinoma, the most widespread form of liver cancer and one of the most common and lethal malignancies, is characterized by poor prognosis, late onset, and a lack of clear-cut diagnostic markers. Novel therapeutic approaches are desperately required to develop effective treatment regimens. Methods: In this study, we attempted to reverse the proliferative capacity of liver cancer cells through employing a 3 – prong approach. We evaluated the antitumorigenic effects of some medicinal plant extracts that contain bioactive phytochemicals. In addition, we used Imatinib – a tyrosine kinase inhibitor (TKI), with human epidermal growth factor receptor (Her2)-specific small interfering RNA(siRNA) species to counteract the Her2-induced proliferative capacity of cancer cells. In our model, we evaluated the extent of activation of apoptotic mechanisms versus the proliferative and antiapoptotic strategies mounted by cancer cells. Results: Our results showed that HepG2 cells treated with 0.5 mM Imatinib exhibited marked downregulation of Her2 expression, upregulation of the proapoptotic marker, BAX and a downregulation of proliferative markers GPC3 and transforming growth factor (TGF)-β (45, 29, 95, and 115 folds, respectively). In the meantime, there was also significant downregulation of Her2, TGF-β, Mcl1, Spp1, GLUL and GPC3 expression and activation of apoptotic system in the cells treated with a mixture of anti-Her2 siRNA, Imatinib along with some selected extracts where the mixture successfully decreased viability of cancer cells. Conclusion: our study reveals the potential of using TKI along with phytochemical therapy and RNA interference as adjuvant regimen for treatment of liver cancer to augment the efficacy of the current control programs, yet, minimizing the side effects by transition to targeted rather than mass therapies.