Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair
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...
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MDPI AG
2023-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/24/5718 |
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| author | Juliana Calheiros Liliana Raimundo João Morais Ana Catarina Matos Sonia Anna Minuzzo Stefano Indraccolo Emília Sousa Marta Correia da Silva Lucília Saraiva |
| author_facet | Juliana Calheiros Liliana Raimundo João Morais Ana Catarina Matos Sonia Anna Minuzzo Stefano Indraccolo Emília Sousa Marta Correia da Silva Lucília Saraiva |
| author_sort | Juliana Calheiros |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T20:56:06Z |
| format | Article |
| id | doaj.art-ccd8f2268ffa4f549c9f5323436bfbd6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T20:56:06Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ccd8f2268ffa4f549c9f5323436bfbd62023-12-22T13:58:40ZengMDPI AGCancers2072-66942023-12-011524571810.3390/cancers15245718Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA RepairJuliana Calheiros0Liliana Raimundo1João Morais2Ana Catarina Matos3Sonia Anna Minuzzo4Stefano Indraccolo5Emília Sousa6Marta Correia da Silva7Lucília Saraiva8LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalDepartment of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, ItalyDepartment of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, ItalyLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade do Porto, 4050-313 Porto, PortugalDysregulation 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.https://www.mdpi.com/2072-6694/15/24/5718xanthone derivativeanticancer agentDNA damage responsePARPi |
| spellingShingle | Juliana Calheiros Liliana Raimundo João Morais Ana Catarina Matos Sonia Anna Minuzzo Stefano Indraccolo Emília Sousa Marta Correia da Silva Lucília Saraiva Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair Cancers xanthone derivative anticancer agent DNA damage response PARPi |
| title | Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |
| title_full | Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |
| title_fullStr | Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |
| title_full_unstemmed | Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |
| title_short | Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |
| title_sort | antitumor activity of the xanthonoside xgac in triple negative breast ovarian and pancreatic cancer by inhibiting dna repair |
| topic | xanthone derivative anticancer agent DNA damage response PARPi |
| url | https://www.mdpi.com/2072-6694/15/24/5718 |
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