Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study.

BACKGROUND: Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. METHODS: Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. RESULTS: 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. CONCLUSION: Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.

MitoQ demonstrates connexin- and p53-mediated cancer chemoprevention in N-nitrosodiethylamine-induced hepatocarcinogenesis rodent model.

Cancer chemoprevention is an approach that offers huge potential for preventing/retarding carcinogenesis. MitoQ is well-known and extensively studied mitochondria-targeted antioxidants for its applications in diseases linked with oxidative stress. In the present study chemopreventive potential of mitoQ was studied with a focus on the role of gap-junctions and p53 at an advanced stage of HCC. BALB/c mice model of hepatocarcinogenesis was established using N-nitrosodiethylamine as a carcinogen (200 mg/kg b. w., cumulative dose, intraperitoneally). The chemopreventive effect of mitoQ was studied by pre-protecting animals with mitoQ (0.125 mg/kg b. w., orally once a week) till the termination of the study. The tumors developed in the course of the study were histopathologically analyzed and statistically evaluated. The mechanistic role of mitoQ was investigated in terms of mitochondrial oxidative stress, expression of 8-OHdG, Cx26, Cx32, p53 and status of gap-junctional intercellular communication (GJIC) in tumors. Chemopreventive activity of mitoQ was evident from improved survival of animals, significantly (p ≤ 0.05) lower tumor multiplicity, tumor incidence and a total number of tumors. MitoQ treatment significantly (p ≤ 0.05) decreased mitochondrial oxidative stress as indicated by reduced mtROS and mtLPO. Increased staining intensity of 8-OHdG and internalization of Cx26, Cx32 which was observed in hepatic tumors was reduced upon mitoQ treatment. Furthermore, the expression of Cx26, Cx32 and p53 was significantly increased along with improvement in GJIC in mitoQ treatment group. MitoQ demonstrated its chemopreventive potential probably by regulating mtROS, connexins and p53 in hepatocarcinogenesis.