Carbenoxolone upregulates TRAIL\TRAILR2 expression and enhances the anti-neoplastic effect of doxorubicin in experimentally induced hepatocellular carcinoma in rats.

Autor: El-Zehery IM; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: imanmanarel-islam@mans.edu.eg., El-Mesery M; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany., El-Sherbiny M; Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt., El Gayar AM; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt., Eisa NH; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Dec 31; Vol. 741, pp. 150876. Date of Electronic Publication: 2024 Oct 24.
DOI: 10.1016/j.bbrc.2024.150876
Abstrakt: Aims: This study investigates the in vivo anticancer activity of carbenoxolone (CBX) and its role in fighting hepatocellular carcinoma (HCC) progression and alleviating resistance against doxorubicin (DOX). Moreover, the molecular mechanism of action of CBX is explored.
Methods: HCC was induced in Sprague Dawley rats via biweekly administration of thioacetamide (TAA) (200 mg/kg) intraperitoneally (i.p.) for 16 weeks after administering a single dose of diethylnitrosamine (DEN) (200 mg/kg, i.p.). A prophylactic model was established by treating rats with i.p. CBX (20 mg/kg/day) for 4 weeks starting on week 13 post-TAA injection. A therapeutic model was established by treating rats with CBX, DOX, or their combination for 7 weeks following 16 weeks of TAA administration. Serum Alpha-fetoprotein (AFP) and biochemical markers of hepatic functions were assessed. Histopathological examinations of hepatic tissues were performed. Immunohistochemical and qRT-PCR analyses were applied to assess the differential expressions of TRAIL/TRAILR2, Bcl-2, TGF-β1, and caspases 3, 8, and 9.
Results: CBX markedly improved hepatic functions, reduced serum AFP levels, and alleviated TAA-induced hepatic histopathological alterations. CBX triggered apoptosis as evident by upregulating apoptotic markers: TRAIL/TRAILR2, caspases 3, 8, and 9, and downregulating the antiapoptotic protein Bcl-2. CBX downregulated TGF-β1. Interestingly, CBX/DOX combination mitigated hepatic damage and induced apoptosis in a way that surpassed DOX-only treatment.
Conclusion: The current study proposes that CBX is a promising anti-tumor compound, which can work effectively under prophylactic and therapeutic modes. Interestingly, CBX enhanced the anti-tumor effect of DOX. CBX exerted these effects via, in part, stimulating TRAIL-induced apoptosis along with attenuating fibrosis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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