{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:14:11Z","timestamp":1784139251751,"version":"3.55.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN261201500032I"],"award-info":[{"award-number":["HHSN261201500032I"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN26100003"],"award-info":[{"award-number":["HHSN26100003"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN2612018000026I"],"award-info":[{"award-number":["HHSN2612018000026I"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA06927"],"award-info":[{"award-number":["CA06927"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1\u03b2 and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist\/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+\/\u2212;Cdkn2a+\/\u2212 mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.<\/jats:p>","DOI":"10.1093\/carcin\/bgac089","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T14:41:27Z","timestamp":1667918487000},"page":"1137-1148","source":"Crossref","is-referenced-by-count":10,"title":["Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma"],"prefix":"10.1093","volume":"43","author":[{"given":"Yuwaraj","family":"Kadariya","sequence":"first","affiliation":[{"name":"Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Sementino","sequence":"additional","affiliation":[{"name":"Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ujjawal","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Gorman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Social and Administrative Sciences, Samford University McWhorter School of Pharmacy , Birmingham, AL, 35229 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M","family":"White","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, MRIGlobal , Kansas City, MO, 64110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A","family":"Ross","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margie L","family":"Clapper","sequence":"additional","affiliation":[{"name":"Cancer Prevention and Control Program, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouri","family":"Neamati","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Michigan , Ann Arbor, MI, 48109 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Steven","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Cancer Prevention, National Cancer Institute , 9606 Medical Center Drive, Rockville, MD, 20850 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1301-5175","authenticated-orcid":false,"given":"Joseph R","family":"Testa","sequence":"additional","affiliation":[{"name":"Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center , Philadelphia, PA, 19111 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"2023042212404636500_CIT0001","doi-asserted-by":"crossref","first-page":"4031","DOI":"10.3390\/ijerph19074031","article-title":"Asbestos and other hazardous fibrous minerals: potential exposure pathways and associated health risks","volume":"19","author":"Berry","year":"2022","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"2023042212404636500_CIT0002","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3322\/caac.21572","article-title":"Mesothelioma: scientific clues for prevention, diagnosis, and therapy","volume":"69","author":"Carbone","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"2023042212404636500_CIT0003","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fonc.2020.00101","article-title":"Preclinical models of malignant mesothelioma","volume":"10","author":"Testa","year":"2020","journal-title":"Front. Oncol."},{"key":"2023042212404636500_CIT0004","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/1940-6207.CAPR-15-0347","article-title":"Inflammation-related IL1beta\/IL1R signaling promotes the development of asbestos-induced malignant mesothelioma","volume":"9","author":"Kadariya","year":"2016","journal-title":"Cancer Prev. Res."},{"key":"2023042212404636500_CIT0005","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/carcin\/bgv174","article-title":"Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice","volume":"37","author":"Pietrofesa","year":"2016","journal-title":"Carcinogenesis"},{"key":"2023042212404636500_CIT0006","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1126\/science.1156995","article-title":"Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica","volume":"320","author":"Dostert","year":"2008","journal-title":"Science"},{"key":"2023042212404636500_CIT0007","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1158\/0008-5472.CAN-13-2062","article-title":"Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis","volume":"74","author":"Menges","year":"2014","journal-title":"Cancer Res."},{"key":"2023042212404636500_CIT0008","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1158\/1535-7163.MCT-12-1082","article-title":"Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer","volume":"12","author":"Xu","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"2023042212404636500_CIT0009","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.bmc.2006.09.073","article-title":"Synthesis and antitumor activities of a series of novel quinoxalinhydrazides","volume":"15","author":"Grande","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"2023042212404636500_CIT0010","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1158\/0008-5472.CAN-14-1328","article-title":"Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma","volume":"74","author":"Xu","year":"2014","journal-title":"Cancer Res."},{"key":"2023042212404636500_CIT0011","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/(SICI)1098-2264(199903)24:3<238::AID-GCC9>3.0.CO;2-M","article-title":"Frequent mutations of NF2 and allelic loss from chromosome band 22q12 in malignant mesothelioma: evidence for a two-hit mechanism of NF2 inactivation","volume":"24","author":"Cheng","year":"1999","journal-title":"Genes Chromosomes Cancer"},{"key":"2023042212404636500_CIT0012","doi-asserted-by":"crossref","first-page":"G59","DOI":"10.1152\/ajpgi.00101.2014","article-title":"Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention","volume":"309","author":"Fajardo","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2023042212404636500_CIT0013","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s10689-022-00292-2","article-title":"Long-term chemoprevention in patients with adenomatous polyposis coli: an observational study","volume":"21","author":"Neuhann","year":"2022","journal-title":"Fam. Cancer"},{"key":"2023042212404636500_CIT0014","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1158\/1940-6207.CAPR-21-0208","article-title":"Suppression of colon tumorigenesis in mutant Apc mice by a novel PDE10 inhibitor that reduces oncogenic beta-catenin","volume":"14","author":"Lee","year":"2021","journal-title":"Cancer Prev. Res."},{"key":"2023042212404636500_CIT0015","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/j.drudis.2020.06.008","article-title":"PDE5 and PDE10 inhibition activates cGMP\/PKG signaling to block Wnt\/beta-catenin transcription, cancer cell growth, and tumor immunity","volume":"25","author":"Piazza","year":"2020","journal-title":"Drug Discov. Today"},{"key":"2023042212404636500_CIT0016","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1158\/1940-6207.CAPR-21-0572","article-title":"The COX-2-PGE2 pathway promotes tumor evasion in colorectal adenomas","volume":"15","author":"Wei","year":"2022","journal-title":"Cancer Prev. Res."},{"key":"2023042212404636500_CIT0017","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1517\/14728222.2013.830105","article-title":"gp130: a promising drug target for cancer therapy","volume":"17","author":"Xu","year":"2013","journal-title":"Expert Opin Ther. Targets"},{"key":"2023042212404636500_CIT0018","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41577-018-0066-7","article-title":"Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer","volume":"18","author":"Jones","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"2023042212404636500_CIT0019","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1042\/BST20180136","article-title":"The role of the interleukin (IL)-6\/IL-6 receptor axis in cancer","volume":"46","author":"Taher","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"2023042212404636500_CIT0020","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.immuni.2019.03.026","article-title":"Targeting interleukin-6 signaling in clinic","volume":"50","author":"Kang","year":"2019","journal-title":"Immunity"},{"key":"2023042212404636500_CIT0021","doi-asserted-by":"crossref","first-page":"4960","DOI":"10.1158\/0008-5472.CAN-19-3044","article-title":"Noncanonical IL6 signaling-mediated activation of YAP regulates cell migration and invasion in ovarian clear cell cancer","volume":"80","author":"Azar","year":"2020","journal-title":"Cancer Res."},{"key":"2023042212404636500_CIT0022","doi-asserted-by":"crossref","first-page":"326","DOI":"10.3390\/cancers12020326","article-title":"GP130 cytokines in breast cancer and bone","volume":"12","author":"Omokehinde","year":"2020","journal-title":"Cancers"},{"key":"2023042212404636500_CIT0023","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000505099","article-title":"Interleukin-6: a masterplayer in the cytokine network","volume":"98","author":"Uciechowski","year":"2020","journal-title":"Oncology"},{"key":"2023042212404636500_CIT0024","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 signalling axis in cancer.","volume":"15","author":"Johnson","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2023042212404636500_CIT0025","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.5858\/2007-131-1350-EOAALS","article-title":"Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: possible role for chemotherapeutic intervention","volume":"131","author":"Achcar Rde","year":"2007","journal-title":"Arch. Pathol. Lab. Med."},{"key":"2023042212404636500_CIT0026","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/bjc.1998.150","article-title":"Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma","volume":"77","author":"Nakano","year":"1998","journal-title":"Br. J. Cancer"},{"key":"2023042212404636500_CIT0027","first-page":"55","article-title":"The role of interleukin-6 in malignant mesothelioma","volume":"4","author":"Abdul Rahim","year":"2015","journal-title":"Transl. Lung Cancer Res."},{"key":"2023042212404636500_CIT0028","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1158\/1078-0432.CCR-14-1233","article-title":"Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival","volume":"20","author":"Dabir","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"2023042212404636500_CIT0029","doi-asserted-by":"crossref","first-page":"173107","DOI":"10.1016\/j.ejphar.2020.173107","article-title":"Targeting STAT3 in cancer and autoimmune diseases","volume":"878","author":"Gharibi","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"2023042212404636500_CIT0030","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3390\/cancers13010007","article-title":"Inhibitors of the transcription factor STAT3 decrease growth and induce immune response genes in models of malignant pleural mesothelioma (MPM)","volume":"13","author":"Lapidot","year":"2020","journal-title":"Cancers"},{"key":"2023042212404636500_CIT0031","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.7150\/thno.41792","article-title":"Up-regulation of hypoxia-inducible factor antisense as a novel approach to treat ovarian cancer","volume":"10","author":"Lu","year":"2020","journal-title":"Theranostics"},{"key":"2023042212404636500_CIT0032","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1093\/carcin\/bgab032","article-title":"Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma","volume":"42","author":"Baumeister","year":"2021","journal-title":"Carcinogenesis"},{"key":"2023042212404636500_CIT0033","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1158\/0008-5472.CAN-15-3371","article-title":"Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations","volume":"76","author":"Kadariya","year":"2016","journal-title":"Cancer Res."}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgac089\/47749337\/bgac089.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/43\/12\/1137\/50064841\/bgac089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/43\/12\/1137\/50064841\/bgac089.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T12:42:27Z","timestamp":1682167347000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/43\/12\/1137\/6820973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,11,10]]},"published-print":{"date-parts":[[2022,12,31]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgac089","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,11,10]]}}}