Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis.

Abstract

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, Il-10, Tgf-β, 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.

• Authors: Mónica G Mendoza-Rodríguez, C Ángel Sánchez-Barrera, Blanca E Callejas, Verónica García-Castillo, Diana L Beristain-Terrazas, Norma L Delgado-Buenrostro, Yolanda I Chirino, Sonia A León-Cabrera, Miriam Rodríguez-Sosa, Emma Bertha Gutierrez-Cirlos, Carlos Pérez-Plasencia, Felipe Vaca-Paniagua, Marco Antonio Meraz-Ríos, Luis I Terrazas
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 6 (Mar 20 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32244885 (Publication Type: Journal Article)

Chemical References

• 4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide
• Adjuvants, Pharmaceutic
• Cadherins
• Cell Adhesion Molecules
• Cytokines
• Pyrimidines
• STAT6 Transcription Factor
• beta Catenin
• Glycine
• Fluorouracil

Topics

• Adjuvants, Pharmaceutic (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Cadherins (metabolism)
• Carcinogenesis (pathology)
• Cell Adhesion Molecules (metabolism)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Survival (drug effects)
• Colitis (complications, pathology)
• Colonic Neoplasms (drug therapy, etiology, pathology)
• Cytokines (metabolism)
• Epithelial Cells (drug effects, metabolism, pathology)
• Female
• Fluorouracil (pharmacology, therapeutic use)
• Glycine (pharmacology, therapeutic use)
• Humans
• Inflammation (pathology)
• Mice, Inbred BALB C
• Monocytes (metabolism)
• Phosphorylation (drug effects)
• Pyrimidines (pharmacology, therapeutic use)
• STAT6 Transcription Factor (metabolism)
• beta Catenin (metabolism)