Autophagy Modulation Attenuates Sorafenib Resistance In HCC Induced In Rats

Abstract

Abstract Hepatocellular carcinoma (HCC) has risen as the villain of cancer-related death globally, with a usual cruel forecasting. For advanced HCC, sorafenib has been FDA approved as first line treatment. In spite of the bright potential that sorafenib demonstrated in studies, actual clinical results are limited owing to the massive occurrence of drug resistance. The tumor microenvironment (TME) has been linked to therapeutic resistance, indicating that current cellular level approaches may be inadequate to increase treatment efficacy. The involvement of autophagy in cancer is a double-edged knife. On one aspect, autophagy allows malignant cells to withstand strain, such as a hypoxic TME and starvation caused by therapy. on the other side, autophagy plays a vital function in damage prevention, which can decrease carcinogenesis. As a result, regulating autophagy is unquestionably a viable method in the therapy of malignancies. The aim if this study was to investigate the role of autophagy modulation in combination to sorafenib by comparing both induction and inhibition of autophagy to the sorafenib monotherapy of HCC induced in Sprague–Dawley rats. Autophagy, apoptosis and cell cycle were analyzed by using western blot, ELISA, Immunuhistochemistry, flow cytometry and Quantitive-PCR. Routine biochemical testing and pathological examination was carried out. Transmission electron microscope was used to visualize ultracellular structures and autophagic bodies. We found remarkable alleviation of chemotherapeutic resistance and hepatoprotective effects by both regimens. To the best of our knowledge, this study was the first to study the autophagic inhibition simultaneous with autophagic induction in sorafenib treatment in-vivo.