The potential chemotherapeutic effect of β-ionone and/or sorafenib against hepatocellular carcinoma via its antioxidant effect, PPAR-γ, FOXO-1, Ki-67, Bax, and Bcl-2 signaling pathways.

Proliferation and apoptosis are two primary driving forces behind the pathogenesis of hepatocellular carcinoma (HCC). HCC is associated with Ki-67 and Bcl-2 overexpression, reduced Bax expression inducing disturbance of equilibrium between cellular proliferation and apoptosis, and exacerbated by reduced expression of PPAR-γ and FOXO-1. Our objective was to examine the mechanism by which the cyclic isoprenoid, β-ionone (βI), attenuated hepatocarcinogenesis and compare its possible anticancer activity with sorafenib (SF) as standard HCC treatment. HCC induction was achieved by supplying Wistar rats with 0.01% diethylnitrosamine (DENA) for 8 consecutive weeks by free access of drinking water. The effects of βI (160 mg/kg/day) administered orally were evaluated by biochemical, oxidative stress, macroscopical, and histopathological analysis. In addition, immunohistochemical assay for localization and expression of Bax and Bcl-2 and RT-PCR for expression levels of PPAR-γ, FOXO-1, and Ki-67 mRNA were performed. βI treatment significantly reduced the incidence, total number, and multiplicity of visible hepatocyte nodules, attenuated LPO, near-normal restoration of all cancer biomarkers, and antioxidant activities, indicating the chemotherapeutic impact of βI. Histopathological analysis of the liver confirmed that further. βI also induced pro-apoptotic protein Bax expression and reduced anti-apoptotic expression of Bcl-2 protein. Moreover, βI induced mRNA expression of tumor suppressor genes (PPAR-γ and FOXO-1) and decreased proliferative marker Ki-67 mRNA expression. For the first time, the present study provides evidence that βI exerts a major anticancer effect on DENA-induced HCC, at least in part, through inhibition of cell proliferation, oxidative stress, and apoptogenic signal induction mediated by downregulation of Bcl-2 and upregulation of Bax, PPAR-γ, and FOXO-1 expressions. [ABSTRACT FROM AUTHOR]