{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T10:56:07Z","timestamp":1779188167426,"version":"3.51.4"},"reference-count":69,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T00:00:00Z","timestamp":1584662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PAPIIT-DGAPA-UNAM","award":["IN226519"],"award-info":[{"award-number":["IN226519"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["A1-S-37879"],"award-info":[{"award-number":["A1-S-37879"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial\u2013mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as \u03b2-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-\u03b2, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.<\/jats:p>","DOI":"10.3390\/ijms21062130","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T07:29:07Z","timestamp":1584689347000},"page":"2130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis"],"prefix":"10.3390","volume":"21","author":[{"given":"M\u00f3nica G.","family":"Mendoza-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. \u00c1ngel","family":"S\u00e1nchez-Barrera","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca E.","family":"Callejas","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Garc\u00eda-Castillo","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana L.","family":"Beristain-Terrazas","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norma L.","family":"Delgado-Buenrostro","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6627-3392","authenticated-orcid":false,"given":"Yolanda I.","family":"Chirino","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia A.","family":"Le\u00f3n-Cabrera","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-9390","authenticated-orcid":false,"given":"Miriam","family":"Rodr\u00edguez-Sosa","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma Bertha","family":"Gutierrez-Cirlos","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8593-8211","authenticated-orcid":false,"given":"Carlos","family":"P\u00e9rez-Plasencia","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"},{"name":"Instituto Nacional de Cancerolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Av. San Fernando No. 22, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2200-9706","authenticated-orcid":false,"given":"Felipe","family":"Vaca-Paniagua","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"},{"name":"Instituto Nacional de Cancerolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Av. San Fernando No. 22, Ciudad de M\u00e9xico 14080, Mexico"},{"name":"Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de Mexico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6748-8117","authenticated-orcid":false,"given":"Marco Antonio","family":"Meraz-R\u00edos","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Avenida IPN 2508, San Pedro Zacatenco, Ciudad de M\u00e9xico 07360, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis I.","family":"Terrazas","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"},{"name":"Laboratorio Nacional en Salud, Facultad de Estudios Superiores Iztacala, Universidad Nacional Aut\u00f3noma de Mexico, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1002\/ijc.31937","article-title":"Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods","volume":"144","author":"Ferlay","year":"2019","journal-title":"Int. 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