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

and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occur 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. 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. 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 downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of cytotoxic T lymphocytes (CTLs), 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 number of tumors and an amelioration of the tumorigenesis process in CAC. Tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease. [Display omitted] •Tigecycline showed an antiproliferative activity targeting the Wnt/β-catenin and STAT3 pathway.•The administration of Tigecycline ameliorated the tumorigenesis process and induced apoptosis.•Tigecycline reduced the cancer-associated inflammation.•Tigecycline treatment positively impacted gut dysbiosis in CAC mice.•Tigecycline would constitute a potential new tool for the management of CRC.