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

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 ß-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-ß, 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.

Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment?

Colorectal cancer (CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence, and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer; thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages III and IV. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors (smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus, the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.