{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:52:10Z","timestamp":1780487530592,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T00:00:00Z","timestamp":1544400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China, CAMS Innovation Fund for Medical Science , China Postdoctoral Science Foundation","award":["30870583, 31670859, 2017-I2M-1-016, 2018M630106"],"award-info":[{"award-number":["30870583, 31670859, 2017-I2M-1-016, 2018M630106"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in clinical radiobiology. However, resistance to radiotherapy for colorectal cancer greatly decreases the therapeutic outcome. Melatonin (N-acetyl-5-methoxytryptamine), a natural secretory product that the pineal gland in the brain normally produces, has been reported to have anticancer properties. In the study, we investigated the combination of melatonin with radiotherapy as a treatment for colorectal cancer. We firstly explored the anti-tumor activity of melatonin combined with ionizing radiation (IR) against colorectal carcinoma in vitro. It was found that melatonin effectively inhibited human colorectal carcinoma cell line HCT 116 cellular proliferation, colony formation rate and cell migration counts following IR. Increasing the radiosensitivity of colorectal cancer cells by melatonin treatment was found to be associated with cell cycle arrest in the G2\/M phase, downregulation of proteins involved in DNA double-strand break repair and activation of the caspase-dependent apoptotic pathway. Moreover, we also investigated the combined effect of IR and melatonin on colorectal tumor in vivo. Results from a tumor xenograft showed that melatonin plus IR treatment significantly suppressed tumor cell growth compared with melatonin or IR alone, resulting in a much higher tumor inhibition rate for the combined treatment. The data suggested that melatonin combined with IR could improve the radiosensitivity of colorectal cancer and thus enhance the therapeutic effect of the patients, implying melatonin could function as a potential sensitizer in tumor radiotherapy.<\/jats:p>","DOI":"10.3390\/ijms19123974","type":"journal-article","created":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T11:31:16Z","timestamp":1544441476000},"page":"3974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Melatonin Sensitizes Human Colorectal Cancer Cells to \u03b3-ray Ionizing Radiation In Vitro and In Vivo"],"prefix":"10.3390","volume":"19","author":[{"given":"Qin","family":"Wang","sequence":"first","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijuan","family":"Sun","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Du","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Xu","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-4518","authenticated-orcid":false,"given":"Bing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"He","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhan","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihua","family":"Ji","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7668-6868","authenticated-orcid":false,"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Key Lab of Radiation Medicine Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ijrobp.2004.02.006","article-title":"Melatonin as a radioprotective agent: A review","volume":"59","author":"Vijayalaxmi","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.neuron.2015.02.016","article-title":"Melatonin is required for the circadian regulation of sleep","volume":"85","author":"Gandhi","year":"2015","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e12370","DOI":"10.1111\/jpi.12370","article-title":"Cancer metastasis: Mechanisms of inhibition by melatonin","volume":"62","author":"Su","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1016\/j.drudis.2014.04.014","article-title":"Melatonin: Functions and ligands","volume":"19","author":"Singh","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.canlet.2015.10.015","article-title":"Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis","volume":"370","author":"Cos","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Gui, S., Zhou, Q., and Wang, Y. (2014). Melatonin inhibits the migration of human lung adenocarcinoma A549 cell lines involving JNK\/MAPK pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101132"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e2432","DOI":"10.1038\/cddis.2016.330","article-title":"Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway","volume":"7","author":"Lu","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/jpi.12285","article-title":"Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-\u03baB activation","volume":"60","author":"Ju","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29606","DOI":"10.1038\/srep29606","article-title":"Urinary melatonin-sulfate\/cortisol ratio and the presence of prostate cancer: A case control study","volume":"6","author":"Tai","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jardim-Perassi, B.V., Arbab, A.S., Ferreira, L.C., Borin, T.F., Varma, N.R., Iskander, A.S., Shankar, A., Ali, M.M., and de Campos Zuccari, D.A. (2014). Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085311"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1600-079X.2010.00823.x","article-title":"Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model","volume":"50","author":"Schmit","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1530\/ERC-15-0463","article-title":"Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma","volume":"23","author":"Chuffa","year":"2016","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fic, M., Gomulkiewicz, A., Grzegrzolka, J., Podhorska-Okolow, M., Zabel, M., Dziegiel, P., and Jablonska, K. (2017). The impact of melatonin on colon cancer cells\u2019resistance to Doxorubicin in an in vitro study. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071396"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.3892\/mmr.2015.3599","article-title":"Effects of ghrelin, leptin and melatonin on the levels of reactive oxygen species, antioxidant enzyme activity and viability of the HCT 116 human colorectal carcinoma cell line","volume":"12","author":"Buldak","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/jpi.12226","article-title":"Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation","volume":"58","author":"Wei","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/jpi.12131","article-title":"Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-\u03baB","volume":"56","author":"Casado","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/jpi.12119","article-title":"Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells","volume":"56","author":"Hong","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1600-079X.2007.00463.x","article-title":"Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture","volume":"43","author":"Escames","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_20","first-page":"1951","article-title":"Biomodulation of cancer chemotherapy for metastatic colorectal cancer: A randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations","volume":"23","author":"Cerea","year":"2003","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1089\/acm.2017.0081","article-title":"Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation","volume":"23","author":"Onseng","year":"2017","journal-title":"J. Altern. Complement. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/jpi.12092","article-title":"Inhibition of matrix metalloproteinase 9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells","volume":"56","author":"Mauriz","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.redox.2018.02.025","article-title":"Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS","volume":"16","author":"Zou","year":"2018","journal-title":"Redox Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1080\/09553002.2018.1446227","article-title":"Therapeutic potential of melatonin for breast cancer radiation therapy patients","volume":"94","author":"Griffin","year":"2018","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"578137","DOI":"10.1155\/2014\/578137","article-title":"Can melatonin help us in radiation oncology treatments?","volume":"2014","author":"Mihandoost","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/ar.21361","article-title":"Role of CD4+ CD25+ regulatory T cells in melatonin-mediated inhibition of murine gastric cancer cell growth in vivo and in vitro","volume":"294","author":"Liu","year":"2011","journal-title":"Anat. Rec. (Hoboken)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.ijrobp.2004.03.005","article-title":"Role of cell cycle in mediating sensitivity to radiotherapy","volume":"59","author":"Pawlik","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1093\/jnci\/88.19.1346","article-title":"DNA repair: Enzymatic mechanisms and relevance to drug response","volume":"88","author":"Chaney","year":"1996","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20810","DOI":"10.1073\/pnas.0807990106","article-title":"Use of the Rad51 promoter for targeted anti-cancer therapy","volume":"105","author":"Hine","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1042\/BST0340633","article-title":"Cellular functions of the BRCA tumour-suppressor proteins","volume":"34","author":"Boulton","year":"2006","journal-title":"Biochem. Soc. Trans."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/jpi.12205","article-title":"Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair","volume":"58","author":"Cos","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3109\/01480545.2012.737805","article-title":"The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells","volume":"36","author":"Kontek","year":"2013","journal-title":"Drug Chem. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1159\/000438587","article-title":"Melatonin induces cell apoptosis in AGS cells through the activation of JNK and P38 MAPK and the suppression of nuclear factor-kappa B: A novel therapeutic implication for gastric cancer","volume":"37","author":"Li","year":"2015","journal-title":"Cell Physiol. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1002\/ar.22689","article-title":"Growth-inhibitory activity of melatonin on murine foregastric carcinoma cells in vitro and the underlying molecular mechanism","volume":"296","author":"Xu","year":"2013","journal-title":"Anat. Rec. (Hoboken)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1600-079X.2009.00682.x","article-title":"Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: Therapeutic implications for prostate cancer","volume":"47","author":"Joo","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/ijc.20837","article-title":"Melatonin potentiates flavones-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products","volume":"116","author":"Wenzel","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1023\/A:1026552405042","article-title":"Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene","volume":"64","author":"Rao","year":"2000","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_38","first-page":"7327","article-title":"Melatonin in patients with cancer receiving chemotherapy: A randomized, double-blind, placebo-controlled trial","volume":"34","author":"Sookprasert","year":"2014","journal-title":"Anticancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:32:46Z","timestamp":1760196766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,10]]},"references-count":38,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["ijms19123974"],"URL":"https:\/\/doi.org\/10.3390\/ijms19123974","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,10]]}}}