Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair

Simple Summary DNA repair inhibition constitutes a promising anticancer strategy, particularly in triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC). XGAc is a xanthonoside previously described as a potent cancer cell growth inhibitor. Herein, we aimed to evaluate the antitumor activity of XGAc in TNBC, ovarian cancer and PDAC cells, either alone or in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. XGAc exhibits antiproliferative activity in TNBC, ovarian cancer and PDAC cells, also proving to be effective against patient-derived ovarian cancer cells and drug-resistant cancer cells. XGAc inhibited cancer cell migration, induced apoptosis and S-phase cell cycle arrest, and triggered genotoxicity by inhibiting the expression of homologous recombination DNA repair proteins in TNBC, ovarian cancer and PDAC cells. Importantly, XGAc displayed synergistic effects with olaparib, demonstrating its potential in combination therapy. Altogether, XGAc reveals itself to be a valuable anticancer agent for hard-to-treat cancers.Abstract Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers.