No abstract

Objective: Cancer remains to be one of the leading causes of death around the world. Modern targeted therapies have undeniably improved cancer patients’ survival, but search still continues for safer and more effective drugs. This work is an attempt to assess the effectiveness of cotreatment of aqueous fruit extract of Morinda citrifolia L. (Noni) on methotrexate (MTX)-induced cytotoxicity on HeLa cancer cell line. Methods: HeLa cells were treated with different concentrations of MTX and Noni alone and in combination for 24 and 48 h and studied for the cytotoxic effects by various approaches. Results: There was a dose-dependent inhibition of growth when treated with MTX in a dose range of 0.045–45.4 μg/ml and Noni for a dose range of 0.3–30 mg/ml for 48 h. The IC50 for MTX was 4.45 μg/ml (1 μM/ml), and for Noni, it was 8 mg/ml while the combination exhibited a more intensive growth inhibitory effect. Our results were confirmed with phase-contrast microscopy, whereby the number of viable cells decreased with an increase in the concentration of Noni. Cells were found to have rounded up and detached from the flask indicating apoptosis. Apoptosis in HeLa cell lines was further confirmed by DNA fragmentation and flow cytometry. Conclusion: It can be concluded that Noni may enhance MTX cytotoxicity by inducing apoptosis and cell cycle arrest. Hence, cotreatment with Noni may reduce the dosage of MTX necessary for inhibiting proliferation of malignant cells and hence decrease the toxic effects of MTX on the system.

Mitochondrial dysfunction has been implicated in the etiology of many drug-induced toxicities. Methotrexate (MTX), an antimetabolite and one of the folic acid antagonists, has widely been used to treat a variety of disorders such as cancer and several autoimmune disorders. It induces oxidative stress which results in many of its ill effects on different target and non-target organs, altering different metabolic pathways and interfering mitochondrial bioenergetics. Here, in our study, we have assessed the toxicity of methotrexate on rat liver mitochondria and its modulation by Morinda citrifolia L. (Noni) fruit extract. MTX significantly affects mitochondrial function, and activity of important mitochondrial enzymes such as Succinate dehydrogenase (SDH), Malate dehydrogenase (MDH) and NADH dehydrogenase. Reduced Cytochrome C-oxidase activity and Reduced glutathione (GSH) levels in MTX treated group (p<0.001) was also observed. An increase in the activity of calcium dependent ATPase (Ca 2+ dependent ATPase) was observed along with increase in lipid peroxidation (lpx), and significant decrease in mitochondrial protein in MTX treated groups. Liver mitochondria of animals administered with Noni extract did not show any toxicity and combination of aqueous Noni fruit extract and methotrexate showed amelioration of toxicity as compared to methotrexate alone. Our study suggests that Noni can have significant protective effect on liver injury induced by MTX. Nutraceutical supplement like antioxidants found in edible plants such as Noni may be a safe and effective way of alleviating the liver toxicity. Hence, we propose that combination of Noni and methotrexate can be potentially safer combination in cancer therapy.