Mitoquinol mesylate (MITOQ) attenuates diethyl nitrosamine-induced hepatocellular carcinoma through modulation of mitochondrial antioxidant defense systems

Abstract

Diethyl nitrosamine (DEN) induced cirrhosis-hepatocellular carcinoma (HCC) model associates cancer progression with oxidative stress and mitochondrial dysfunction. This study investigated the effects of mitoquinol mesylate (MitoQ), a mitochondrial-targeted antioxidant on DEN-induced oxidative damage in HCC Wistar rats. Fifty male Wistar rats were randomly divided into five groups. Healthy control, DEN, and MitoQ groups were orally administered exactly 10 mg/kg of distilled water, DEN, and MitoQ, respectively for 16 weeks. Animals in the MitoQ + DEN group were pre-treated with MitoQ for a week followed by co-administration of 10 mg/kg each of MitoQ and DEN. DEN + MitoQ group received DEN for 8 weeks, then co-administration of 10 mg/kg each of DEN and MitoQ till the end of 16th week. Survival index, tumour incidence, hematological profile, liver function indices, lipid profile, mitochondrial membrane composition, mitochondrial respiratory enzymes, and antioxidant defense status in both mitochondrial and post-mitochondrial fractions plus expression of antioxidant genes were assessed. In MitoQ + DEN and DEN + MitoQ groups, 80% survival occurred while tumour incidence decreased by 60% and 40% respectively, compared to the DEN-only treated group. Similarly, MitoQ-administered groups showed a significant (p < 0.05) decrease in the activities of liver function enzymes while hemoglobin concentration, red blood cell count, and packed cell volume were significantly elevated compared to the DEN-only treated group. Administration of MitoQ to the DEN-intoxicated groups successfully enhanced the activities of mitochondrial F₁F₀-ATPase and succinate dehydrogenase; and up-regulated the expression and activities of SOD2, CAT, and GPx1. Macroscopic and microscopic features indicated a reversal of DEN-induced hepatocellular degeneration in the MitoQ + DEN and DEN + MitoQ groups. These data revealed that MitoQ intervention attenuated DEN-induced oxidative stress through modulation of mitochondrial antioxidant defense systems and alleviated the burden of HCC as a chemotherapeutic agent.

Keywords: Antioxidant enzymes; Diethyl nitrosamine; Hepatocellular carcinoma; MitoQ; Oxidative stress.

Fig. 1

Experimental design

Fig. 2

Macroscopic features and photomicrographs of hepatoma rats treated with MitoQ. The black arrows in the MitoQ + DEN and DEN + MitoQ groups indicate cirrhotic cells; the black arrows in the DEN group show focus containing malignant cells, Magnification- × 250; Healthy control— × 100. Control—healthy control group; DEN—group received only DEN; MitoQ—animals administered only MitoQ; MitoQ + DEN—animals pre-treated with MitoQ for a week followed by co-administration of MitoQ and DEN for 16 weeks; DEN + MitoQ—group administered DEN for 8 weeks followed by co-administration of DEN and MitoQ for the remaining 8 weeks

Fig. 3

Effects of MitoQ on the specific activities of mitochondrial respiratory enzymes in HCC rats. Succinate dehydrogenase (SDH) activity (a), F1F0-ATPase enzyme activity (b). Values are expressed as means ± SEM. Bars not sharing a common alphabet differ significantly at p < 0.05. DEN diethyl nitrosamine, MitoQ mitoquinol mesylate, HCC hepatocellular carcinoma

Fig. 4

Effects of MitoQ on the expression of SOD2 (a), CAT (b), and GPX1 (c) GPx genes in HCC rats. Values are expressed as means ± SEM. Bars not sharing a common alphabet differ significantly at p < 0.05. DEN diethyl nitrosamine, MitoQ mitoquinol mesylate, HCC hepatocellular carcinoma, GPx glutathione peroxidase

Fig. 5

Effects of MitoQ on the specific activities of SOD (a), CAT (b), GPx1 (c), and the levels of GSH (d) and MDA (e) in the liver mitochondria of HCC rats orally administered MitoQ for 16 weeks. Values are expressed as means ± SEM. Bars not sharing a common alphabet are significantly different at p < 0.05. DEN diethyl nitrosamine, MitoQ mitoquinol mesylate, HCC hepatocellular carcinoma

Fig 6

Effects of MitoQ on the specific activities of SOD (a), CAT (b), GPx1 (c),and the levels of GSH (d) and MDA (e) in the liver post mitochondrial fraction of HCC rats orally administered MitoQ for 16 weeks. Values are expressed as means ± SEM. Bars not sharing a common alphabet are significantly different at p < 0.05. DEN diethyl nitrosamine, MitoQ mitoquinol mesylate, HCC hepatocellular carcinoma, SOD superoxide dismutase, CAT catalase, GPx 1 glutathione peroxidase 1, GSH glutathione, MDA malondialdehyde