Ellagic Acid Induces\nDNA Damage and Apoptosis in Cancer\nStem-like Cells and Overcomes Cisplatin Resistance

Cancer stem cells (CSCs) are responsible for chemoresistance\nand\ntumor relapse in many solid malignancies, including lung and ovarian\ncancer. Ellagic acid (EA), a natural polyphenol, exhibits anticancer\neffects on various human malignancies. However, its impact and mechanism\nof action on cancer stem-like cells (CSLCs) are only partially understood.\nIn this study, we evaluated the therapeutic potential and underlying\nmolecular mechanism of EA isolated from tropical mango against CSLCs.\nHerein, we observed that EA treatment reduces the stem-like phenotypes\nin cancer cells, thereby lowering the cell survival and self-renewal\npotential of ovarian and lung CSLCs. Additionally, EA treatment limits\nthe populations of lung and ovarian CSLCs characterized by CD133<sup>+</sup> and CD44<sup>+</sup>CD117<sup>+</sup>, respectively. A mechanistic\ninvestigation showed that EA treatment induces ROS generation by altering\nmitochondrial dynamics, causing changes in the levels of Drp1 and\nMfn2, which lead to an increased level of accumulation of DNA damage\nand eventually trigger apoptosis in CSLCs. Moreover, pretreatment\nwith EA sensitizes CSLCs to cisplatin treatment by enhancing DNA damage\naccumulation and impairing the DNA repair ability of the CSLCs. Furthermore,\nEA pretreatment significantly reduces cisplatin-induced mutation frequency\nand improves drug retention in CSLCs, potentially suppressing the\ndevelopment of acquired drug resistance. Taken together, our results\ndemonstrate an unreported finding that EA inhibits CSLCs by targeting\nmitochondrial function and triggering apoptosis. Thus, EA can be used\neither alone or in combination with other chemotherepeutic drugs\nfor the management of cancer.