Dual regulating of mitochondrial fusion and Timp-3 by leflunomide and diallyl disulfide combination suppresses diethylnitrosamine-induced hepatocellular tumorigenesis in rats.

Autor: Abdel-Hamid NM; Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt., Abass SA; Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. Electronic address: shimaa_abass@pharm.kfs.edu.eg., Eldomany RA; Department of Microbiology and Immunology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt., Abdel-Kareem MA; Department of Anatomy and Embryology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt., Zakaria S; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2022 Apr 01; Vol. 294, pp. 120369. Date of Electronic Publication: 2022 Feb 01.
DOI: 10.1016/j.lfs.2022.120369
Abstrakt: Aims: Hepatocellular carcinoma (HCC) is considered one of the main causes of cancer-related death globally. Combination therapy targeting different pathways can improve the efficacy of HCC management. Mitofusin 2 (Mfn2), a mitochondrial fusion protein, and a tissue inhibitor of matrix metalloproteinase 3 (Timp-3) were found to be downregulated in various cancers, including HCC. Our study aimed to evaluate the possible antineoplastic effect of a novel combination in the treatment of HCC through targeting mitochondrial fusion and metastatic proteins.
Main Methods: HCC induction was performed using a single intraperitoneal dose of diethylnitrosamine (200 mg/kg), followed by adding phenobarbital sodium (0.05%) to the drinking water for successive 18 weeks. Then, leflunomide (LF, 10 mg/kg) was administered orally for 28 days. Diallyl disulfide (DADS, 50 mg/kg) was also given orally for 28 days, either alone or in combination with LF.
Key Findings: Treatment with LF or DADS could alleviate the HCC- induced histological and biochemical variations, including liver enzyme activities (ALT, AST), alpha-fetoprotein, Bax, cyclin D1, Ki67, malondialdehyde, and reduced glutathione. They could shift the mitochondrial dynamics toward mitochondrial fusion through upregulating the expression of Mfn2 and also exhibited antimetastatic activity through upregulating the expression of Timp-3 and decreasing hepatic MMP9 content.
Significance: the treatment with a combination of LF and DADS displayed a more potent effect than the treatment with each drug alone. Our results suggest that the combined use of LF and a naturally occurring DADS can be used as a promising novel combination in managing HCC.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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