Research Papers:

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

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

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Oncotarget. 2016; 7:26361-26373. https://doi.org/10.18632/oncotarget.8379

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Maria Buoncervello1, Giulia Romagnoli1,*, Mariachiara Buccarelli1,*, Alessandra Fragale1, Elena Toschi1, Stefania Parlato1, Donatella Lucchetti2, Daniele Macchia1, Massimo Spada1, Irene Canini1, Massimo Sanchez3, Mario Falchi4, Martina Musella1, Mauro Biffoni1, Filippo Belardelli1, Imerio Capone1, Alessandro Sgambato2, Lucia Ricci Vitiani1, Lucia Gabriele1

1Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

2Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy

3Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

4National AIDS Center, Istituto Superiore di Sanità, Rome, Italy

*These authors have contributed equally to this work

Correspondence to:

Lucia Gabriele, email: [email protected]

Keywords: colorectal cancer, cancer stem cell, interferon, epigenetics, immunogenic cell death

Received: October 08, 2015     Accepted: March 02, 2016     Published: March 25, 2016


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.

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