{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:18:40Z","timestamp":1787725120998,"version":"build-2784847793"},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008467","name":"Canadian Association of Radiation Oncology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008467","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose\u2010escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP\u2010activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl\u2010CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Androgen\u2010insensitive (PC3) and \u2010sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb\/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5\u2009g\/kg salsalate (SAL pro\u2010drug dimer) one week prior to a single dose of 0 or 10\u2009Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK\u2010mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti\u2010tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa in combination with RT.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.23755","type":"journal-article","created":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T18:42:52Z","timestamp":1546627372000},"page":"489-497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Salicylate enhances the response of prostate cancer to radiotherapy"],"prefix":"10.1002","volume":"79","author":[{"given":"Lindsay A.","family":"Broadfield","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Marcinko","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Tsakiridis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Department of Oncology McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panayiotis G.","family":"Zacharidis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"},{"name":"Department of Oncology McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Villani","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S. V.","family":"Lally","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabe","family":"Menjolian","sequence":"additional","affiliation":[{"name":"Division of Radiotherapy Juravinski Cancer Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danitra","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Division of Radiotherapy Juravinski Cancer Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Mathurin","sequence":"additional","affiliation":[{"name":"Division of Radiotherapy Juravinski Cancer Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia","family":"Smoke","sequence":"additional","affiliation":[{"name":"Division of Radiotherapy Juravinski Cancer Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Farrell","sequence":"additional","affiliation":[{"name":"Division of Physics Juravinski Cancer Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Muti","sequence":"additional","affiliation":[{"name":"Department of Oncology McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory R.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8675-4422","authenticated-orcid":false,"given":"Theodoros","family":"Tsakiridis","sequence":"additional","affiliation":[{"name":"Department of Oncology McMaster University Hamilton Ontario Canada"},{"name":"Divisions of Radiation Oncology Juravinski Cancer Center Hamilton Ontario Canada"},{"name":"Department of Pathology and Molecular Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,1,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.8475"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.10.1233"},{"key":"e_1_2_8_4_1","first-page":"130","article-title":"Association between nonsteroidal anti\u2010inflammatory drugs and prostate cancer occurrence","volume":"12","author":"Dasgupta K","year":"2006","journal-title":"Cancer J"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.649.13.4"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11255-014-0703-4"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dji173"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11250"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq175"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.227"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2012.09.030"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-12-55"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60209-8"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24890"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.28554"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.41.0308"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-16-1027"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.5301\/tj.5000424"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2012.02.050"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2013.01.036"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2013.06.002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12940"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1215327"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17496"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.26726"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2008"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20150122"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.630"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3372"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.03.027"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2010.03.005"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.187"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1981.tb06218.x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0564"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2017.5353"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1159\/000464434"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06149-4"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(02)00519-0"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.7397"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-1338"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-152-6-201003160-00004"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1752-8062.2008.00026.x"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.003"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204252"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716173114"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.051011"}],"container-title":["The Prostate"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpros.23755","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.23755","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T21:53:14Z","timestamp":1694728394000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pros.23755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,4]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1002\/pros.23755"],"URL":"https:\/\/doi.org\/10.1002\/pros.23755","archive":["Portico"],"relation":{},"ISSN":["0270-4137","1097-0045"],"issn-type":[{"value":"0270-4137","type":"print"},{"value":"1097-0045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,4]]},"assertion":[{"value":"2018-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}