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.
Highlights
Many nutraceuticals and plant active compounds are an important historical and ethnobotanical source for developing drugs with broad-spectrum pharmacological activities such as anticancer, antitumor, and antioxidant
Aqueous fruit extract from Morinda citrifolia L. (Noni), which has a diverse array of active phytoconstituents with multitude of pharmacological activities, has been used for cotreatment in our study
After 16 h, the medium from the well was replaced with medium containing different concentrations of M. citrifolia L. fruit extract (0.3–30 mg/ml)
Summary
Many nutraceuticals and plant active compounds are an important historical and ethnobotanical source for developing drugs with broad-spectrum pharmacological activities such as anticancer, antitumor, and antioxidant. An increasing incidence of cancer in developing and developed countries has promoted research toward dietary and medicinal plant extracts as supplements and prophylactics essentially due to the presence of phenolic acids, flavonoids, and phenolic diterpenes [1]. Usage of alternative medicine is a necessity of the hour as they can be protective and can possess antioxidant and antitumor agents which can be more effective and reduce toxicity due to the presence of phytochemicals [2,3]. (Noni), which has a diverse array of active phytoconstituents with multitude of pharmacological activities, has been used for cotreatment in our study. Noni is used as an herbal remedy and has promising antioxidant properties [4]
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