Seane, Elsie NeoNair, ShankariVandevoorde, CharlotBisio, AlessandraJoubert, Anna Margaretha2025-04-242025-04-242024-11-01Seane, E.N.; Nair, S.; Vandevoorde, C.; Bisio, A.; Joubert, A. Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line. Pharmaceuticals 2024, 17, 1467. https://DOI.org/10.3390/ph17111467.1424-824710.3390/ph17111467http://hdl.handle.net/2263/102208DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author.SUPPLEMENTARY MATERIALS : FIGURE S1: Representative images for apoptosis profiles; FIGURE S2: Representative images of the cell cycle profile after different treatment conditions.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.en© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.CUDC-101Proton therapyProton irradiationHistone deacetylase inhibitors (HDCAi)Histone deacetylases (HDACs)Human epidermal growth factor receptor 2 (HER-2)Epidermal growth factor receptor (EGFR)SDG-03: Good health and well-beingArticle