Targeting p53/TRAIL/caspase-8 signaling by adiponectin reverses thioacetamide-induced hepatocellular carcinoma in rats.

Autor: Nazmy EA; Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., El-Khouly OA; Dep. of Pharmaceutical Organic Chemistry, Faculty of Pharmacy,Mansoura University, Mansoura, Egypt., Zaki MMA; Dep. of Pathology, Faculty of Medicine, Mansoura University, Egypt., Elsherbiny NM; Dep. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia., Said E; Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: emansaid@mans.edu.eg., Al-Gayyar MMH; Dep. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia., Salem HA; Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Jazyk: angličtina
Zdroj: Environmental toxicology and pharmacology [Environ Toxicol Pharmacol] 2019 Nov; Vol. 72, pp. 103240. Date of Electronic Publication: 2019 Aug 07.
DOI: 10.1016/j.etap.2019.103240
Abstrakt: Given the enormous impact of HCC on the patients' quality of life and healthcare economics, the current study was conducted to investigate the potential ability of adiponectin to reverse established HCC and to investigate the underlying mechanisms which control the chemotherapeutic and hepatoprotective effects. HCC was induced in Male Sprague Dawely rats by I.P. injection of thioacetamide(200 mg/kg) 3 times/week for 14 weeks.HCC development was confirmed by histopathological examination and assessment of serum levels of α-fetoprotein (AFP). Adiponectin was administered (5 μg/kg, I.P.) starting from week 13 of the experiment and for further 4 weeks. Adiponectinadministration revealed a significant antitumor activity with significant improvement in liver functions and oxidative status. Nevertheless, pathological features as cirrhosis, dysplastic changes, and tumoral nodules were significantly attenuated with significant enhancement in hepatic caspase-3 immunostaining. Mechanistically, adiponectin administration was associated with significant restoration of p53 activity; which increased by 133%, with a reduction in HCC-induced expression of-JNK which decreased by 53%as well as a significant enhancement of hepatic TRAIL and caspase-8 activities which increased by 27% and 20% respectively. In conclusion; Adiponectin can be proposed as a promising therapy for HCC. Adiponectin's tumoricidal activity can be partially mediated by blocking HCC-induced reduction in p53 expression as well as reactivation of TRAIL signaling and induction of apoptotic pathway providing more protection for the body against the tumor.
(Copyright © 2019 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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