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.