Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico.
Instituto Nacional de Cancerología, Subdirección de Investigación Básica, Av. San Fernando No. 22, Ciudad de México 14080, Mexico.
Int J Mol Sci. 2020 Mar 20;21(6):2130. doi: 10.3390/ijms21062130.
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-mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, , and , 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.
结直肠癌（CRC）是全球最广泛和最致命的肿瘤类型之一，其中炎症微环境在肿瘤生长、转移和耐药过程中具有重要意义。尽管氟尿嘧啶（5-FU）的疗效有限，但它仍是 CRC 治疗的主要药物。将 5-FU 与其他药物联合使用可适度提高其在患者中的疗效。在这里，我们评估了具有抗炎作用的三甲基甘氨酸和信号转导和转录激活因子（STAT6）抑制剂 AS1517499，作为 5-FU 在已建立的癌症中的辅助药物，使用结肠炎相关结肠癌（CAC）模型。我们发现，当这些辅助疗法与 5-FU 一起使用时，可显著抑制肿瘤生长，这与 STAT6 磷酸化的减少有关。这种减少通过增加细胞凋亡和细胞黏附标志物（如 E-钙黏蛋白）的水平来增强 5-FU 的作用，而降低上皮-间充质转化标志物与侵袭性表型和耐药性相关，如β-连环蛋白核转位和锌指蛋白 SNAI1（SNAI1）。此外，这些辅助疗法还下调了结肠中关键的促肿瘤细胞因子，如、和。在体外人结肠癌细胞实验中，三甲基甘氨酸也可降低 STAT6 磷酸化。我们的研究相对独特之处在于，重点研究了 AS1517499 和三甲基甘氨酸联合 5-FU 联合给药对已建立的 CAC 的影响，这种联合作用可显著降低结肠肿瘤负荷。总之，这些数据表明 STAT6 是结肠癌辅助治疗的一个有价值的靶点。
