{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:59:51Z","timestamp":1775609991647,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scienti\ufb01c Research","award":["15K10705 and 19K09834"],"award-info":[{"award-number":["15K10705 and 19K09834"]}]},{"name":"Grant-in-Aid for Scienti\ufb01c Research C","award":["17K11268"],"award-info":[{"award-number":["17K11268"]}]},{"name":"Grant-in-Aid for Scienti\ufb01c Research C","award":["18K09249"],"award-info":[{"award-number":["18K09249"]}]},{"name":"Grant-in-Aid for Research Activity start-up","award":["16H06757"],"award-info":[{"award-number":["16H06757"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.<\/jats:p>","DOI":"10.3390\/cancers11121913","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T10:50:45Z","timestamp":1575283845000},"page":"1913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"Makoto","family":"Takeuchi","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michihiro","family":"Tanikawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0696-5175","authenticated-orcid":false,"given":"Kazunori","family":"Nagasaka","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"},{"name":"Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-8605, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2468-9573","authenticated-orcid":false,"given":"Katsutoshi","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiko","family":"Kawata","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Oki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7325-1167","authenticated-orcid":false,"given":"Chuwa","family":"Agapiti","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenbun","family":"Sone","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-8605, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruko","family":"Hiraike","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-8605, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Wada-Hiraike","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Kuramoto","sequence":"additional","affiliation":[{"name":"Kanagawa Health Service Association, Yokohama 231-0021, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Ayabe","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-8605, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Osuga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0090-8258(83)90111-7","article-title":"Two pathogenetic types of endometrial carcinoma","volume":"15","author":"Bokhman","year":"1983","journal-title":"Gynecol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1093\/oxfordjournals.aje.a114414","article-title":"Conjugated estrogen use and risk of endometrial cancer","volume":"124","author":"Buring","year":"1986","journal-title":"Am. J. Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Brinton, L.A., Lacey, J.V., and Sherman, M.E. (2005). Epidemiology of Gynecologic Cancers. Principles and Practice of Gynecologic Oncology, Lippincott Williams & Wilkins. [4th ed.].","DOI":"10.1016\/B978-0-443-07142-3.50018-X"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ygyno.2014.01.032","article-title":"The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance","volume":"133","author":"Ko","year":"2014","journal-title":"Gynecol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"The Research Group for Population-Based Cancer Registration in Japan (2003). Cancer incidence and incidence rates in Japan in 1998: Estimates based on data from 12 population-based cancer registries. JPN J. Clin. Oncol., 33, 241\u2013245.","DOI":"10.1093\/jjco\/hyg044"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1200\/JCO.2004.00.7617","article-title":"Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: A Gynecologic Oncology Group Study","volume":"24","author":"Randall","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"vi35","DOI":"10.1093\/annonc\/mdr374","article-title":"Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"22","author":"Colombo","year":"2011","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/S0140-6736(12)60442-5","article-title":"Contemporary management of endometrial cancer","volume":"379","author":"Wright","year":"2012","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0090-8258(91)90086-K","article-title":"Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study","volume":"40","author":"Morrow","year":"1991","journal-title":"Gynecol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1016\/S0140-6736(00)02139-5","article-title":"Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma","volume":"355","author":"Creutzberg","year":"2000","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/cas.12366","article-title":"Targeting DNA damage response in cancer therapy","volume":"105","author":"Hosoya","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.pharmthera.2014.12.001","article-title":"ATM and ATR as therapeutic targets in cancer","volume":"149","author":"Weber","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrc1691","article-title":"The concept of synthetic lethality in the context of anticancer therapy","volume":"5","author":"Kaelin","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nrc3342","article-title":"The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance","volume":"12","author":"Bouwman","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/nrc3399","article-title":"DNA repair dysregulation from cancer driver to therapeutic target","volume":"12","author":"Curtin","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8127","DOI":"10.1158\/0008-5472.CAN-08-0755","article-title":"PIK3CA cooperates with other phosphatidylinositol 3\u2019-kinase pathway mutations to effect oncogenic transformation","volume":"68","author":"Oda","year":"2008","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/ng.2007.80","article-title":"Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling","volume":"40","author":"Griffith","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nrc1296","article-title":"Targeting the checkpoint kinases: Chemosensitization versus chemoprotection","volume":"4","author":"Zhou","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/B978-0-12-380888-2.00003-0","article-title":"The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer","volume":"108","author":"Smith","year":"2010","journal-title":"Adv. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1126\/science.7792600","article-title":"A single ataxia telangiectasia gene with a product similar to PI-3 kinase","volume":"268","author":"Savitsky","year":"1995","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1146\/annurev.immunol.15.1.177","article-title":"The genetic defect in ataxia-telangiectasia","volume":"15","author":"Lavin","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a012716","DOI":"10.1101\/cshperspect.a012716","article-title":"DNA damage sensing by the ATM and ATR kinases","volume":"5","author":"Zou","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2015.10.040","article-title":"Targeting the DNA damage response in cancer","volume":"60","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ygyno.2014.12.035","article-title":"Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells","volume":"136","author":"Teng","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nchembio.573","article-title":"Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR","volume":"7","author":"Reaper","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1038\/onc.2013.275","article-title":"ATM signalling and cancer","volume":"33","author":"Cremona","year":"2014","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nature11547","article-title":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","volume":"491","author":"Biankin","year":"2012","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1046\/j.1365-2559.2003.01713.x","article-title":"Altered expression of DNA double-strand break detection and repair proteins in breast carcinomas","volume":"43","author":"Angele","year":"2003","journal-title":"Histopathology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1158\/1055-9965.EPI-082-3","article-title":"Ataxia-telangiectasia-mutated (ATM) gene in head and neck squamous cell carcinoma: Promoter hypermethylation with clinical correlation in 100 cases","volume":"13","author":"Ai","year":"2004","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.lungcan.2009.03.011","article-title":"Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features","volume":"65","author":"Kim","year":"2009","journal-title":"Lung Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/sj.onc.1205207","article-title":"Concomitant inactivation of p53 and Chk2 in breast cancer","volume":"21","author":"Sullivan","year":"2002","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.celrep.2015.12.032","article-title":"Cancer-specific synthetic lethality between ATR and CHK1 kinase activities","volume":"14","author":"Sanjiv","year":"2016","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4129","DOI":"10.1128\/MCB.21.13.4129-4139.2001","article-title":"ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1","volume":"21","author":"Zhao","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30537","DOI":"10.1074\/jbc.M104414200","article-title":"The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation","volume":"276","author":"Lee","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nsmb.2076","article-title":"A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations","volume":"18","author":"Toledo","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/cddis.2012.181","article-title":"Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation","volume":"3","author":"Fokas","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ctrv.2013.03.002","article-title":"Targeting ATR in DNA damage response and cancer therapeutics","volume":"40","author":"Fokas","year":"2014","journal-title":"Cancer Treat. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9152","DOI":"10.1158\/0008-5472.CAN-04-2727","article-title":"Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM","volume":"64","author":"Hickson","year":"2004","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2894","DOI":"10.1158\/1535-7163.MCT-09-0519","article-title":"Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion","volume":"8","author":"Golding","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1158\/1078-0432.CCR-12-3408","article-title":"ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation","volume":"19","author":"Sajjad","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1200\/JCO.2008.19.9802","article-title":"ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes","volume":"27","author":"Zighelboim","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1007\/s13277-014-2712-4","article-title":"ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway","volume":"36","author":"Shan","year":"2015","journal-title":"Tumour. Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/12\/1913\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:39:12Z","timestamp":1760189952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/12\/1913"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cancers11121913"],"URL":"https:\/\/doi.org\/10.3390\/cancers11121913","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,1]]}}}