title: Myricetin Selectively Induces Apoptosis on Cancerous Hepatocytes by Directly Targeting Their Mitochondria.
abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. In patients for whom HCC could not be detected early, current treatments show poor tolerance and low efficacy. So, alternative therapies with good efficacy are urgently needed. The aim of this research was to evaluate the selective apoptotic effects of myricetin (MYR), a flavonoid compound, on hepatocytes and mitochondria obtained from the liver of HCC rats. In this study, HCC induced by diethylnitrosamine (DEN), as an initiator, and 2-acetylaminofluorene (2-AAF), as a promoter. To confirm the HCC induction, serum levels of alpha-fetoprotein (AFP), AST, AST and ALP and histopathological changes in the liver tissue were evaluated. Rat liver hepatocytes and mitochondria for evaluation of the selective cytotoxic effects of MYR were isolated, and mitochondrial and cellular parameters related to apoptosis signalling were then determined. Our results showed that MYR was able to induce cytotoxicity only in hepatocytes from the HCC but not from the untreated control group. Besides, MYR (12.5, 25 and 50 μM) induced a considerable increase in reactive oxygen species (ROS) level, mitochondrial swelling, mitochondrial membrane permeabilization (MMP) and cytochrome c release only in cancerous but not in untreated normal hepatocyte mitochondria. MYR selectively increased caspase-3 activation and apoptotic phenotypes in HCC, but not untreated normal hepatocytes. Finally, our finding underlines MYR as a promising therapeutic candidate against HCC and recommends the compound for further studies.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Enayatollah
authors.initials: E
authors.lastname: Seydi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Rasekh
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.|Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salimi
authors.affiliation: Faculty of Medicine, Ayatollah Taleghani Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Zhaleh
authors.initials: Z
authors.lastname: Mohsenifar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Jalal
authors.initials: J
authors.lastname: Pourahmad
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D005419:Flavonoids; D017382:Reactive Oxygen Species; D000509:alpha-Fetoproteins; D004052:Diethylnitrosamine; C040015:myricetin; D045304:Cytochromes c; D015073:2-Acetylaminofluorene; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C505410:Casp3 protein, rat; D053148:Caspase 3