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Rafoxanide negatively modulates STAT3 and NF-κB activity and inflammation-associated colon tumorigenesis.
Pacifico, Teresa; Stolfi, Carmine; Tomassini, Lorenzo; Luiz-Ferreira, Anderson; Franzè, Eleonora; Ortenzi, Angela; Colantoni, Alfredo; Sica, Giuseppe S; Sambucci, Manolo; Monteleone, Ivan; Monteleone, Giovanni; Laudisi, Federica.
Afiliación
  • Pacifico T; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Stolfi C; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Tomassini L; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Luiz-Ferreira A; Inflammatory Bowel Disease Research Laboratory, Department of Biological Sciences, Institute of Biotechnology, Federal University of Catalão (UFCAT), Catalão, Brazil.
  • Franzè E; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Ortenzi A; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Colantoni A; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Sica GS; Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
  • Sambucci M; Neuroimmunology Unit, Santa Lucia Foundation IRCCS, Rome, Italy.
  • Monteleone I; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
  • Monteleone G; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
  • Laudisi F; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Cancer Sci ; 2024 Sep 06.
Article en En | MEDLINE | ID: mdl-39239848
ABSTRACT
In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancer Sci Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancer Sci Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido