A multitude of plants have been used extensively for the treatment of cancers throughout the world. In many parts of the world, especially in poor countries, this may be the only form of cancer therapy. Much research has been focused on the scientific evaluation of traditional anti-cancer drugs from the tropical plant; Momordica charantia (MC) is one of them and it has been used frequently as an anti-cancer agent. The green leaves, fruits, seeds and stems of M. charantia composed of many different proteins and steroids that are chemically active. These proteins are α and β momorcharins which possess anti-cancer and anti-HIV properties similar to crude water and methanol soluble extracts of M. charantia. This study investigated the anti cancer effect of either the crude water and methanol soluble extract of M. charantia, α and β and α, β momorcharins based on dose-dependent, time-dependent on the viability of 1321N1, Gos-3, U87-MG, Sk Mel, Corl -23, Weri Rb-1 and L6 cell lines employing different concentrations of each extract or drug. In addition, the study measured the effect of either temozolomide or vinblastine alone or combining each with either the crude water soluble extract of M. charantia or α β momorcharin measuring cell viability in the different cell lines. Furthermore, the present study investigated the cellular mechanism(s) via which the different anti-cancer agents were able to induce cell death measuring the activities of caspase - 3 and caspase - 9, the release of cytochrome c and intracellular free calcium concentrations [Ca 2+ ]i. The results have shown that the crude water soluble extract of M. charantia can evoke both time-course at (800 µg) and dose-dependent (200 µg - 800 µg) decreases in cell viability with maximal increases with 800 µg over a period of 24 hrs following incubation. Either the crude methanol soluble of M. charantia (200 µg - 800 µg), alpha or beta momorcharin (200 µM - 800 µM) had little or no effect on the viability of the different cell lines. In contrast, either alpha, beta momorcharin (200 µM - 800 µM), temozolomide (80 µM - 320 µM) or vinblastine (10 μg - 40 μg) can evoke significant (p < 0.05) decrease in cell viability, similar to the crude water soluble extract of M. charantia. The results also show that combining either temozolomide (240 µM) or vinblastine (40 μg) with either (800 µg) of the crude water- soluble extract of M. charantia or (800 µM) of alpha, beta momorcharin can result in significant decreases in cell viability for each cell line but these effects were neither additive or synergetic compared to the individual effect of temozolomide or vinblastine. The result of this study have also shown that either the crude water-soluble extract of M. charantia (800 µg) or (800 µM) of alpha, beta momorcharin can elicit marked and significant (p < 0.050 increases in the activities of caspase - 3 and caspase - 9 in all the cell lines. Similarly, both the crude water soluble extract of M. charantia and alpha, beta momorcharin can stimulate the release of cytochrome-c and elevated [Ca2+ ]i in the different cancer cell lines compared to untreated cell lines. Together, the results of the study have shown that either the crude water soluble extract of M. charantia or alpha, beta momorcharin can exert their anti-cancer effects (cell death) on cancer cell lines by increasing the activities of caspase - 3 and caspase - 9 and by releasing cytochrome-c and elevating [Ca2+ ]i in the cancer cells. These findings implicate the role of apoptosis and cellular Ca 2+ homeostasis in cancer cell death. Moreover, they confirm the beneficial use of extracts of M. charantia to treat cancers.