{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:00:36Z","timestamp":1778644836857,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Project of Yancheng","award":["YCBK2024008"],"award-info":[{"award-number":["YCBK2024008"]}]},{"name":"Natural Science Foundation of the Jiangsu Higher Education Institutions of China","award":["21KJB360013"],"award-info":[{"award-number":["21KJB360013"]}]},{"name":"Jiangsu Medical College Innovative Research Team for Science and Technology","award":["20254305"],"award-info":[{"award-number":["20254305"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) cells with intact homologous recombination (HR) repair mechanism can survive treatment with Olaparib, which further limits the clinical application of PARP1\/2 inhibitors. Previous studies have demonstrated that inhibition of indoleamine 2,3-dioxygenase (IDO) can enhance the sensitivity of human tumor cells to PARP1\/2 inhibitors. However, the mechanisms underlying their synergistic effects in the treatment of TNBC remain unclear. Herein, we demonstrate that the combination of Olaparib and Epacadostat significantly reduces the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared to either monotherapy. Mechanistically, Epacadostat reduces intracellular kynurenine and NAD+ levels, thereby sensitizing TNBCs to PARP1\/2 inhibition and significantly amplifying Olaparib-induced DNA damage. Furthermore, Epacadostat and Olaparib synergistically increase cellular reactive oxygen species (ROS), leading to DNA oxidative damage and apoptosis. In vivo, Epacadostat and Olaparib significantly suppressed MDA-MB-468 tumor growth compared to the monotherapy groups, while promoting an increase in phosphorylated H2AX. Notably, the dual inhibition of IDO1 and PARP1\/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1\/2 represents a promising combination therapy for BRCA-proficient TNBC.<\/jats:p>","DOI":"10.3390\/molecules31061039","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:44:41Z","timestamp":1773999881000},"page":"1039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epacadostat and Olaparib Synergistically Inhibit the Growth of BRCA-Proficient Triple-Negative Breast Cancer by Suppressing the Expression of BRCA1 and RAD51"],"prefix":"10.3390","volume":"31","author":[{"given":"Lei","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Medicinal Chemistry, Jiangsu Medical College, Yancheng 224005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Medicinal Chemistry, Jiangsu Medical College, Yancheng 224005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongxia","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Jiangsu Medical College, Yancheng 224005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Jiangsu Medical College, Yancheng 224005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingxin","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjun","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Medicinal Chemistry, Jiangsu Medical College, Yancheng 224005, China"},{"name":"Department of Preventive Medicine, Jiangsu Medical College, Yancheng 224005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1056\/NEJMoa2409932","article-title":"Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer","volume":"391","author":"Schmid","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.3892\/ijo.2020.5135","article-title":"Triple-negative breast cancer therapy: Current and future perspectives","volume":"57","author":"Won","year":"2020","journal-title":"Int. J. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13058-020-01296-5","article-title":"Triple-negative breast cancer molecular subtyping and treatment progress","volume":"22","author":"Yin","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_4","first-page":"3865","article-title":"Leukocyte\/platelet hybrid membrane-camouflaged dendritic large pore mesoporous silica nanoparticles co-loaded with photo\/chemotherapeutic agents for triple negative breast cancer combination treatment","volume":"6","author":"Zhang","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/s41419-021-04434-9","article-title":"FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41568-022-00535-5","article-title":"Targeting DNA damage response pathways in cancer","volume":"23","author":"Groelly","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108625","DOI":"10.1016\/j.celrep.2020.108625","article-title":"RAD52 Adjusts Repair of Single-Strand Breaks via Reducing DNA-Damage-Promoted XRCC1\/LIG3\u03b1 Co-localization","volume":"34","author":"Wang","year":"2021","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1038\/s41416-022-01946-9","article-title":"CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer","volume":"127","author":"Hsieh","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12929-019-0507-z","article-title":"Loss of NFBD1\/MDC1 disrupts homologous recombination repair and sensitizes nasopharyngeal carcinoma cells to PARP inhibitors","volume":"26","author":"Wang","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41419-022-04670-7","article-title":"HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer","volume":"13","author":"Ma","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4774","DOI":"10.1038\/s41598-021-82990-y","article-title":"BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression","volume":"11","author":"Li","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.18632\/oncotarget.1916","article-title":"Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin","volume":"5","author":"Vareki","year":"2014","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1158\/1541-7786.MCR-19-0239","article-title":"Targeting the kynurenine pathway for the treatment of cisplatin-resistant lung cancer","volume":"18","author":"Nguyen","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s41419-022-05021-2","article-title":"IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma","volume":"13","author":"Sun","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1016\/j.febslet.2009.04.005","article-title":"BRCA1 down-regulates cellular levels of reactive oxygen species","volume":"583","author":"Saha","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4115","DOI":"10.1038\/s41467-018-06586-3","article-title":"ROS-induced R loops trigger a transcription-coupled but BRCA1\/2-independent homologous recombination pathway through CSB","volume":"9","author":"Teng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, J., Tao, J., Ling, Y., Li, F., Zhu, X., Xu, L., Wang, M., Zhang, S., McCall, C.E., and Liu, T.F. (2019). Switch of NAD salvage to denovo biosynthesis sustains SIRT1-RelB-dependent inflammatory tolerance. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02358"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tian, X., Chen, L., Gai, D., He, S., Jiang, X., and Zhang, N. (2022). Adverse event profiles of PARP Inhibitors: Analysis of spontaneous reports submitted to FAERS. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.851246"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1126\/science.aad8242","article-title":"A conserved NAD+ binding pocket that regulates protein-protein interactions during aging","volume":"355","author":"Li","year":"2017","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, S., Sun, B., Wang, D., Liu, Y., Li, J., Qi, J., Zhang, Y., Bai, C., and Liang, S. (2021). Chlorogenic acid ameliorates damage induced by fluorene-9-bisphenol in porcine sertoli cells. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.678772"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Al-Taie, Z., Hannink, M., Mitchem, J., Papageorgiou, C., and Shyu, C.R. (2021). Drug repositioning and subgroup discovery for precision medicine implementation in triple negative breast cancer. Cancers, 13.","DOI":"10.3390\/cancers13246278"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12943-015-0289-1","article-title":"Prognostic relevance of acquired uniparental disomy in serous ovarian cancer","volume":"14","author":"Tuna","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.7150\/ijbs.16176","article-title":"The correlation between PARP1 and BRCA1 in AR positive triple-negative breast cancer","volume":"12","author":"Luo","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41388-024-03227-6","article-title":"Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: Overcoming resistance mechanisms","volume":"44","author":"Jain","year":"2025","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10732748241298329","DOI":"10.1177\/10732748241298329","article-title":"Update on combination strategies of PARP inhibitors","volume":"31","author":"Lin","year":"2024","journal-title":"Cancer Control"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"807","DOI":"10.4049\/jimmunol.1302913","article-title":"Tryptophan catabolism restricts IFN-\u03b3-expressing neutrophils and Clostridium difficile immunopathology","volume":"193","author":"Chang","year":"2014","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1093\/nar\/gkv1476","article-title":"Single molecule detection of PARP1 and PARP2 interaction with DNA strand breaks and their poly (ADP-ribosyl)ation using high-resolution AFM imaging","volume":"44","author":"Sukhanova","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41388-021-02105-9","article-title":"Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress","volume":"41","author":"Hao","year":"2022","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"32329","DOI":"10.18632\/oncotarget.8617","article-title":"Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.2147\/OTT.S138123","article-title":"Reactive oxygen species mediate soft corals-derived sinuleptolide-induced antiproliferation and DNA damage in oral cancer cells","volume":"10","author":"Chang","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112860","DOI":"10.1016\/j.isci.2025.112860","article-title":"Mechanistic study of N-acetyltransferase 10 deficiency enhancing olaparib sensitivity in triple negative breast cancer by inhibiting RAD51 N4-acetylcytidine modification","volume":"28","author":"Li","year":"2025","journal-title":"iScience"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e0224321","DOI":"10.1128\/mBio.02243-21","article-title":"The epstein-barr virus oncogene EBNA1 suppresses natural killer cell responses and apoptosis early after infection of peripheral B cells","volume":"12","author":"Smith","year":"2021","journal-title":"mBio"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41419-022-04989-1","article-title":"DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage","volume":"13","author":"Shih","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4632","DOI":"10.1038\/s41467-019-12610-x","article-title":"ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer","volume":"10","author":"Kanakkanthara","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/0168-9525(96)10019-6","article-title":"Genetic manipulation of genomes with rare-cutting endonucleases","volume":"12","author":"Jasin","year":"1996","journal-title":"Trends Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.2147\/IJN.S287806","article-title":"A carrier-free folate receptor-targeted ursolic acid\/methotrexate nano delivery system for synergetic anticancer therapy","volume":"16","author":"Lan","year":"2021","journal-title":"Int. J. Nanomed."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/6\/1039\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:45:28Z","timestamp":1773999928000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/6\/1039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["molecules31061039"],"URL":"https:\/\/doi.org\/10.3390\/molecules31061039","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]}}}