IFN-α potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer

Donatella Lucchetti, Alessandro Sgambato, Maria Buoncervello, Giulia Romagnoli, Mariachiara Buccarelli, Alessandra Fragale, Elena Toschi, Stefania Parlato, Daniele Macchia, Massimo Spada, Irene Canini, Massimo Sanchez, Mario Falchi, Martina Musella, Mauro Biffoni, Filippo Belardelli, Imerio Capone, Lucia Ricci Vitiani, Lucia Gabriele

Risultato della ricerca: Contributo in rivistaArticolo in rivista

12 Citazioni (Scopus)

Abstract

Epigenetic alterations, including dysregulated DNA methylation and histone modifications, govern the progression of colorectal cancer (CRC). Cancer cells exploit epigenetic regulation to control cellular pathways, including apoptotic and metastatic signals. Since aberrations in epigenome can be pharmacologically reversed by DNA methyltransferase and histone deacetylase inhibitors, epigenetics in combination with standard agents are currently envisaged as a new therapeutic frontier in cancer, expected to overcome drug resistance associated with current treatments. In this study, we challenged this idea and demonstrated that the combination of azacitidine and romidepsin with IFN-α owns a high therapeutic potential, targeting the most aggressive cellular components of CRC, such as metastatic cells and cancer stem cells (CSCs), via tight control of key survival and death pathways. Moreover, the antitumor efficacy of this novel pharmacological approach is associated with induction of signals of immunogenic cell death. Of note, a previously undisclosed key role of IFN-α in inducing both antiproliferative and pro-apoptotic effects on CSCs of CRC was also found. Overall, these findings open a new frontier on the suitability of IFN-α in association with epigenetics as a novel and promising therapeutic approach for CRC management.
Lingua originaleEnglish
pagine (da-a)26361-26373
Numero di pagine13
RivistaOncotarget
Volume7
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Cancer stem cell
  • Colorectal cancer
  • Epigenetics
  • Immunogenic cell death
  • Interferon
  • Oncology

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