Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response.

Abstract

Background and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occurs in almost 80% of patients. This mutation leads to β-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines. Experimental Approach: The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies. Key Results: Tigecycline showed an antiproliferative activity targeting the Wnt/β-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through a downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of CD8+ T lymphocytes, one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the numbers of tumors and an amelioration of the tumorigenesis process in CAC. Conclusion and Implications: tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.

Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells

“…Although Tig/Tet has been successfully shown to reduce tumor growth in vivo in various xenograft models, including those derived from prostate, renal, and gastric cancer cells [37,42,45], the lack of in vivo investigation, especially using an immune-competent CRC animal model, remains a major limitation of these studies, including ours. However, a recent report on CRC has shown that tigecycline treatment inhibits tumorigenesis both in vitro and in a colitis-associated colorectal cancer (CAC) murine model [46]. This tumor inhibitory effect is mediated via inhibition of Wnt/βcatenin pathway, apoptosis induction, and reduction of the cancer immune response in the CAC model.…”