Ellagic Acid Induces DNA Damage and Apoptosis in Cancer Stem-like Cells and Overcomes Cisplatin Resistance

Cancer stem cells (CSCs) are responsible for chemoresistance and tumor relapse in many solid malignancies, including lung and ovarian cancer. Ellagic acid (EA), a natural polyphenol, exhibits anticancer effects on various human malignancies. However, its impact and mechanism of action on cancer stem-like cells (CSLCs) are only partially understood. In this study, we evaluated the therapeutic potential and underlying molecular mechanism of EA isolated from tropical mango against CSLCs. Herein, we observed that EA treatment reduces the stem-like phenotypes in cancer cells, thereby lowering the cell survival and self-renewal potential of ovarian and lung CSLCs. Additionally, EA treatment limits the populations of lung and ovarian CSLCs characterized by CD133⁺ and CD44⁺CD117⁺, respectively. A mechanistic investigation showed that EA treatment induces ROS generation by altering mitochondrial dynamics, causing changes in the levels of Drp1 and Mfn2, which lead to an increased level of accumulation of DNA damage and eventually trigger apoptosis in CSLCs. Moreover, pretreatment with EA sensitizes CSLCs to cisplatin treatment by enhancing DNA damage accumulation and impairing the DNA repair ability of the CSLCs. Furthermore, EA pretreatment significantly reduces cisplatin-induced mutation frequency and improves drug retention in CSLCs, potentially suppressing the development of acquired drug resistance. Taken together, our results demonstrate an unreported finding that EA inhibits CSLCs by targeting mitochondrial function and triggering apoptosis. Thus, EA can be used either alone or in combination with other chemotherepeutic drugs for the management of cancer.