Anticancer Therapeutic Potential of Mitochondria‐Targeted Antioxidants Against N‐Nitrosodiethylamine ‐Induced Hepatocarcinogenesis

Mitochondria-targeted antioxidants (MTAs) accumulate in mitochondria to mitigate mitochondrial oxidative stress. The present study investigates the anticancer therapeutic potential of two MTAs, MitoQ, and Mito-TEMPO, in rodent N-nitrosodiethylamine-induced hepatic cancer. Tumor-bearing male Wistar rats were treated with MitoQ (0.125 mg/kg b.w. orally), Mito-TEMPO (0.100 mg/kg b.w. intraperitoneally), or their combination for 6 weeks. The therapeutic effects of these MTAs were assessed in terms of total tumor number, multiplicity, and dielectric properties. Inflammatory level, DNA damage, apoptotic, and cell proliferation markers were assessed using ELISA and immunohistochemistry. Mitochondrial oxidative stress, activities of mitochondrial antioxidant enzymes, and electron transport chain enzymes were assessed using biochemical methods. Results revealed a significant (p ≤ 0.05) reduction in total number of tumors and tumor multiplicity, improved mitochondrial antioxidant system, electron transport, membrane potential and a significant (p ≤ 0.05) decrease in mitochondrial LPO and mitochondrial ROS when compared to untreated Tumor group. Furthermore, treatment significantly (p ≤ 0.05) modulated the levels of IL-6, TNF-α, 8-OHdG, bax, caspase-3, PCNA, Ki67, connexin, and cadherin proteins in tumors. In conclusion, both MitoQ and Mito-TEMPO have appreciable anticancer therapeutic potential against N-nitrosodiethylamine-induced hepatic cancer. The combination treatment of these two MTAs also exhibited additive anticancer therapeutic potential on tumor profile. Therefore, MTA-based anticancer therapy approach holds a promising future.