Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line
Background: Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation or chemotherapeutic drugs in the management of breast cancer....
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MDPI AG
2024-11-01
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| author | Elsie Neo Seane Shankari Nair Charlot Vandevoorde Alessandra Bisio Anna Joubert |
| author_facet | Elsie Neo Seane Shankari Nair Charlot Vandevoorde Alessandra Bisio Anna Joubert |
| author_sort | Elsie Neo Seane |
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| description | Background: Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation or chemotherapeutic drugs in the management of breast cancer. However, studies on the combination of HDACi and proton radiation remain limited. CUDC-101 is a multitarget inhibitor of Histone deacetylases (HDACs), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2). In this paper, the effectiveness of CUDC-101 in enhancing radiation response to both proton and X-ray irradiation was studied. Methods: MCF-7, MDA-MB-231, and MCF-10A cell lines were pre-treated with CUDC-101 and exposed to 148 MeV protons, and X-rays were used as reference radiation. Colony survival, γ-H2AX foci, apoptosis, and cell cycle analysis assays were performed. Results: γ-H2AX foci assays showed increased sensitivity to CUDC-101 in the MDA-MB-231 cell line compared to the MCF-7 cell line. In both cell lines, induction of apoptosis was enhanced in CUDC-101 pre-treated cells compared to radiation (protons or X-rays) alone. Increased apoptosis was also noted in CUDC-101 pre-treated cells in the MCF-10A cell line. Cell cycle analysis showed increased G2/M arrest by CUDC-101 mono-treatment as well as combination of CUDC-101 and X-ray irradiation in the MDA-MB-231 cell line. Conclusions: CUDC-101 effectively enhances response to both proton and X-ray irradiation, in the triple-negative MDA-MB-231 cell line. This enhancement was most notable when CUDC-101 was combined with proton irradiation. This study highlights that CUDC-101 holds potential in the management of triple-negative breast cancer as monotherapy or in combination with protons or X-ray irradiation. |
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| issn | 1424-8247 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-bb96c7c5a6604a32ba72fbf2dcbd4fd02025-08-20T01:53:57ZengMDPI AGPharmaceuticals1424-82472024-11-011711146710.3390/ph17111467Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell LineElsie Neo Seane0Shankari Nair1Charlot Vandevoorde2Alessandra Bisio3Anna Joubert4Department of Radiography, School of Health Care Sciences, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South AfricaSeparate Sector Cyclotron (SSC) Laboratory, Radiation Biophysics Division, iThemba LABS, Cape Town 7530, South AfricaDepartment of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung, 64291 Darmstadt, GermanyDepartment of Cellular, Computational and Integrative Biology, Via Sommarive, 9, Povo, 38123 Trento, ItalyDepartment of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South AfricaBackground: Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation or chemotherapeutic drugs in the management of breast cancer. However, studies on the combination of HDACi and proton radiation remain limited. CUDC-101 is a multitarget inhibitor of Histone deacetylases (HDACs), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2). In this paper, the effectiveness of CUDC-101 in enhancing radiation response to both proton and X-ray irradiation was studied. Methods: MCF-7, MDA-MB-231, and MCF-10A cell lines were pre-treated with CUDC-101 and exposed to 148 MeV protons, and X-rays were used as reference radiation. Colony survival, γ-H2AX foci, apoptosis, and cell cycle analysis assays were performed. Results: γ-H2AX foci assays showed increased sensitivity to CUDC-101 in the MDA-MB-231 cell line compared to the MCF-7 cell line. In both cell lines, induction of apoptosis was enhanced in CUDC-101 pre-treated cells compared to radiation (protons or X-rays) alone. Increased apoptosis was also noted in CUDC-101 pre-treated cells in the MCF-10A cell line. Cell cycle analysis showed increased G2/M arrest by CUDC-101 mono-treatment as well as combination of CUDC-101 and X-ray irradiation in the MDA-MB-231 cell line. Conclusions: CUDC-101 effectively enhances response to both proton and X-ray irradiation, in the triple-negative MDA-MB-231 cell line. This enhancement was most notable when CUDC-101 was combined with proton irradiation. This study highlights that CUDC-101 holds potential in the management of triple-negative breast cancer as monotherapy or in combination with protons or X-ray irradiation.https://www.mdpi.com/1424-8247/17/11/1467Histone deacetylase inhibitorsCUDC-101proton therapyproton irradiation |
| spellingShingle | Elsie Neo Seane Shankari Nair Charlot Vandevoorde Alessandra Bisio Anna Joubert Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line Pharmaceuticals Histone deacetylase inhibitors CUDC-101 proton therapy proton irradiation |
| title | Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line |
| title_full | Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line |
| title_fullStr | Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line |
| title_full_unstemmed | Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line |
| title_short | Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line |
| title_sort | multi target inhibitor cudc 101 impairs dna damage repair and enhances radiation response in triple negative breast cell line |
| topic | Histone deacetylase inhibitors CUDC-101 proton therapy proton irradiation |
| url | https://www.mdpi.com/1424-8247/17/11/1467 |
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