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Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response.
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  • Antonio Jesús Ruiz-Malagón,
  • Laura Hidalgo Garcia,
  • Maria Jesús Rodríguez-Sojo,
  • Jose Alberto Molina-Tijeras,
  • Federico Garcia,
  • Patricia Diez-Echave,
  • Teresa Vezza,
  • Patricia Becerra,
  • Juan Marchal,
  • Eduardo Redondo,
  • Martin Haussmann,
  • Gerhard Rogler,
  • Jose Garrido-Mesa,
  • Maria Elena Rodriguez-Cabezas,
  • Alba Rodríguez-Nogales,
  • Julio Galvez
Antonio Jesús Ruiz-Malagón
CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada
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Laura Hidalgo Garcia
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, 18011
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Maria Jesús Rodríguez-Sojo
CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada
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Jose Alberto Molina-Tijeras
University of Granada
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Federico Garcia
Complejo Hospitalario Universitario de Granada
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Patricia Diez-Echave
CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada
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Teresa Vezza
University of Granada
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Patricia Becerra
Hospital Universitario San Cecilio
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Juan Marchal
University of Granada
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Eduardo Redondo
Hospital Universitario Virgen de las Nieves
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Martin Haussmann
University of Zurich
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Gerhard Rogler
University of Zurich
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Jose Garrido-Mesa
CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada
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Maria Elena Rodriguez-Cabezas
University of Granada

Corresponding Author:[email protected]

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Alba Rodríguez-Nogales
1 CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada
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Julio Galvez
University of Granada
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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.