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Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting
Juliana Calheiros1, Liliana Raimundo1, João Morais1
1LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, Portugal.
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.
Insights
The xanthonoside XGAc shows potent anticancer effects against triple-negative breast, ovarian, and pancreatic cancers. It synergizes with olaparib, inhibits DNA repair, and prevents cancer cell migration, offering hope for hard-to-treat cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- DNA damage response (DDR) dysregulation can sensitize cancer cells to DNA-targeting agents.
- Inhibiting DNA repair pathways is a promising anticancer strategy, especially in combination therapies.
- Xanthonoside XGAc is a known inhibitor of cancer cell growth.
Purpose of the Study:
- To investigate the antitumor activity of XGAc against triple-negative breast cancer (TNBC), ovarian cancer, and pancreatic ductal adenocarcinoma (PDAC).
- To evaluate XGAc as a single agent and in combination with the PARP inhibitor olaparib.
- To explore XGAc's mechanisms of action, including its effects on DNA repair and cell death.
Main Methods:
- Cell viability assays were performed on TNBC, ovarian, and PDAC cell lines.
- Cell cycle arrest and apoptosis were assessed.
- Expression of DNA repair proteins (BRCA1, BRCA2, RAD51) was analyzed.
- Synergistic effects with olaparib were evaluated.
- XGAc's activity was tested in a TNBC spheroid model and patient-derived ovarian cancer cells.
- Drug-resistant cell lines were used to assess cross-resistance.
- Cell migration assays were conducted.
Main Results:
- XGAc inhibited the growth of TNBC, ovarian, and PDAC cells by inducing cell cycle arrest and apoptosis.
- XGAc induced genotoxicity and inhibited key DNA repair proteins (BRCA1, BRCA2, RAD51).
- XGAc demonstrated significant synergistic effects with olaparib in all tested cancer types.
- XGAc's efficacy was confirmed in a TNBC spheroid model and patient-derived ovarian cancer cells.
- Drug-resistant cancer cells did not exhibit cross-resistance to XGAc.
- XGAc effectively inhibited cancer cell migration.
Conclusions:
- XGAc exhibits potent anticancer activity against TNBC, ovarian, and PDAC cells through cell cycle arrest, apoptosis, and inhibition of DNA repair.
- XGAc shows strong synergistic effects when combined with olaparib, highlighting its potential in combination therapy.
- XGAc is effective against drug-resistant cancer cells and inhibits cancer cell migration.
- XGAc represents a promising therapeutic agent for hard-to-treat cancers, including TNBC, ovarian, and pancreatic cancers.
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