Journal d'oncologie intégrative

Novel Angiotens in Receptor Blocker, Azilsartan Induces Oxidative Stress and NFkB-Mediated Apoptosis in Hepatocellular Carcinoma cell line HEPG2

Abstract

W. Robert Liu

Overexpression of Renin-Angiotensin System (RAS) and Nuclear Factor-Kappa B (NF-kB) has a key role in various cancers. Blockade of RAS and NF-kB pathway has been suggested to reduce cancer cell proliferation. This study aimed to investigate the role of angiotensin II and NF-kB pathway in liver Hepatocellular Carcinoma Cell Line (HepG2) proliferation by using azilsartan (as a novel Ag II antagonist) and Bay11-7082 (as NF-kB inhibitor). HepG2 cells were treated with different concentrations of azilsartan and Bay11- 7082. Cytotoxicity was determined after 24, 48, and 72 h by MTT assay. Reactive Oxygen Spices (ROS) generation and cytochrome c release were measured following azilsartan and Bay11-7082 treatment. Apoptosis was analyzed qualitatively by DAPI staining and quantitatively through flow cytometry methodologies and Bax and Bcl-2 mRNA and protein levels were assessed by real-time PCR and ELISA methods, respectively. The cytotoxic effects of different concentration of azilsartan and Bay11-7082 on HepG2 cells were observed as a reduction in cell viability, ROS formation, cytochrome c release, and apoptosis induction. These effects were found to correlate with a shift in Bax level and a downward trend in the expression of Bcl-2. These findings suggest that azilsartan and Bay 11- 7082 in combination or alone have strong potential for development as an agent for prevention against liver cancer after further studies. Hepatocellular carcinoma is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol, aflatoxin, or pyrrolizidine alkaloids. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC. As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, how far the cancer has spread, and overall health. The vast majority of HCC and lowest survival rate after