Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair.
Juliana CalheirosLiliana RaimundoJoão MoraisAna Catarina MatosSonia Anna MinuzzoStefano IndraccoloMaria Emília SousaMarta Correia da SilvaLucília SaraivaPublished in: Cancers (2023)
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.
Keyphrases
- dna repair
- cell cycle arrest
- cell death
- dna damage response
- dna damage
- pi k akt
- induced apoptosis
- drug resistant
- signaling pathway
- cell migration
- multidrug resistant
- oxidative stress
- poor prognosis
- papillary thyroid
- cell proliferation
- squamous cell carcinoma
- cystic fibrosis
- risk assessment
- pseudomonas aeruginosa
- palliative care
- endothelial cells
- young adults
- quality improvement
- childhood cancer