Abstract
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.
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AMA and AMM conceived and designed research. MA and AMM conducted experiments and contributed new reagents or analytical tools. MA and OMA analyzed data. MA wrote the manuscript. All authors read and approved the manuscript.
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All experimental procedures are in accordance with the guidelines and instructions of the Experimental Animal Ethics Committee for care and use of animals, Faculty of Science, Beni-Suef University, Egypt (Ethical Approval Number: BSU/FS/2016/16).
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Abd-Elbaset, M., Mansour, A.M., Ahmed, O.M. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1611–1624 (2020). https://doi.org/10.1007/s00210-020-01863-9
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DOI: https://doi.org/10.1007/s00210-020-01863-9