title: Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma.
abstract: We investigated the possible therapeutic effect of irreversible proteasome inhibitor, carfilzomib against hepatocellular carcinoma induced chemically by chronic administration of diethylnitrosoamines (DENA). Hepatocellular carcinoma induced by DENA in male Wistar rats was manifested biochemically by significant elevation of serum α-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic cancer was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) content were also observed, along with a profound decrease in hepatic endostatin and metallothionein level. Treatment of rats with the selected doses of carfilzomib produced a significant protection against hepatic cancer. The present results claimed that chosen doses of carfilzomib succeeded in suppressing serum tumor markers level AFP and CEA. Furthermore, the drug reduced the elevated level of hepatic growth factors, MMP-2 and TIMP-1 induced by the carcinogen. The antitumor effect of carfilzomib was also accompanied by augmentation of hepatic content of endostatin and metallothionein. Histopathological examination of liver tissues also correlated with the biochemical observations. It could be concluded that treatment with carfilzomib confers a possible antitumor effect against hepatocellular carcinoma induced by DENA model in rats.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, P.O. Box 3660, Riyadh 11426, Saudi Arabia. Electronic address: mansour1960us@yahoo.com.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Mansour
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aljoufi
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Khaled
authors.initials: K
authors.lastname: Al-Hosaini
authors.affiliation: Department of Pathology, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia.
authors.forename: Ammar C
authors.initials: AC
authors.lastname: Al-Rikabi
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Nagi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004052:Diethylnitrosamine / Q000633:toxicity; D043169:Endostatins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens; D043169:Endostatins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D004052:Diethylnitrosamine; C524865:carfilzomib; D008668:Metallothionein; D020778:Matrix Metalloproteinase 2; D046988:Proteasome Endopeptidase Complex
keywords: Carfilzomib; Hepatocellular carcinoma; Proteasome inhibitor