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.

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“…Then, dimethyl sulfoxide (100 μL) was used to dissolve the formazan crystals, and the absorbance was next measured with an enzyme-linked immunosorbent assay reader at 570 nm (Tecan, Rainbow Thermo, Austria). [33,34]…”

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“…After two weeks, liver cancer development was promoted with a once-daily oral administration of 2-AAF (30 mg/kg body weight) for two weeks. HCC was confirmed by histopathological evaluations and the measurement of liver damage and cancer markers, including alfa-fetoprotein (AFP), gamma glutamyl transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) (Seydi et al, 2016[ 34 ]).…”

Development of Asialoglycoprotein Receptor-Targeted Nanoparticles for Selective Delivery of Gemcitabine to Hepatocellular Carcinoma

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