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UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response

Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Despite recent progress, the prognosis of advanced stage CRC remains poor, mainly because of cancer recurrence and metastasis. The high morbidity and mortality of CRC has been recently ascribed to a small population of t...

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Autores principales: Signore, Michele, Buccarelli, Mariachiara, Pilozzi, Emanuela, De Luca, Gabriele, Cappellari, Marianna, Fanciulli, Maurizio, Goeman, Frauke, Melucci, Elisa, Biffoni, Mauro, Ricci-Vitiani, Lucia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190083/
https://www.ncbi.nlm.nih.gov/pubmed/27286453
http://dx.doi.org/10.18632/oncotarget.9859
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author Signore, Michele
Buccarelli, Mariachiara
Pilozzi, Emanuela
De Luca, Gabriele
Cappellari, Marianna
Fanciulli, Maurizio
Goeman, Frauke
Melucci, Elisa
Biffoni, Mauro
Ricci-Vitiani, Lucia
author_facet Signore, Michele
Buccarelli, Mariachiara
Pilozzi, Emanuela
De Luca, Gabriele
Cappellari, Marianna
Fanciulli, Maurizio
Goeman, Frauke
Melucci, Elisa
Biffoni, Mauro
Ricci-Vitiani, Lucia
author_sort Signore, Michele
collection PubMed
description Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Despite recent progress, the prognosis of advanced stage CRC remains poor, mainly because of cancer recurrence and metastasis. The high morbidity and mortality of CRC has been recently ascribed to a small population of tumor cells that hold the potential of tumor initiation, i.e. cancer stem cells (CSCs), which play a pivotal role in cancer recurrence and metastasis and are not eradicated by current therapy. We screened CRC-SCs in vitro with a library of protein kinase inhibitors and showed that CRC-SCs are resistant to specific inhibition of the major signaling pathways involved in cell survival and proliferation. Nonetheless, broad-spectrum inhibition by the staurosporin derivative UCN-01 blocks CRC-SC growth and potentiates the activity of irinotecan in vitro and in vivo CRC-SC-derived models. Reverse-Phase Protein Microarrays (RPPA) revealed that, albeit CRC-SCs display individual phospho-proteomic profiles, sensitivity of CRC-SCs to UCN-01 relies on the interference with the DNA damage response mediated by Chk1. Combination of LY2603618, a specific Chk1/2 inhibitor, with irinotecan resulted in a significant reduction of CRC-SC growth in vivo, confirming that irinotecan treatment coupled to inhibition of Chk1 represents a potentially effective therapeutic approach for CRC treatment.
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spelling pubmed-51900832017-01-05 UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response Signore, Michele Buccarelli, Mariachiara Pilozzi, Emanuela De Luca, Gabriele Cappellari, Marianna Fanciulli, Maurizio Goeman, Frauke Melucci, Elisa Biffoni, Mauro Ricci-Vitiani, Lucia Oncotarget Research Paper Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Despite recent progress, the prognosis of advanced stage CRC remains poor, mainly because of cancer recurrence and metastasis. The high morbidity and mortality of CRC has been recently ascribed to a small population of tumor cells that hold the potential of tumor initiation, i.e. cancer stem cells (CSCs), which play a pivotal role in cancer recurrence and metastasis and are not eradicated by current therapy. We screened CRC-SCs in vitro with a library of protein kinase inhibitors and showed that CRC-SCs are resistant to specific inhibition of the major signaling pathways involved in cell survival and proliferation. Nonetheless, broad-spectrum inhibition by the staurosporin derivative UCN-01 blocks CRC-SC growth and potentiates the activity of irinotecan in vitro and in vivo CRC-SC-derived models. Reverse-Phase Protein Microarrays (RPPA) revealed that, albeit CRC-SCs display individual phospho-proteomic profiles, sensitivity of CRC-SCs to UCN-01 relies on the interference with the DNA damage response mediated by Chk1. Combination of LY2603618, a specific Chk1/2 inhibitor, with irinotecan resulted in a significant reduction of CRC-SC growth in vivo, confirming that irinotecan treatment coupled to inhibition of Chk1 represents a potentially effective therapeutic approach for CRC treatment. Impact Journals LLC 2016-06-06 /pmc/articles/PMC5190083/ /pubmed/27286453 http://dx.doi.org/10.18632/oncotarget.9859 Text en Copyright: © 2016 Signore et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Signore, Michele
Buccarelli, Mariachiara
Pilozzi, Emanuela
De Luca, Gabriele
Cappellari, Marianna
Fanciulli, Maurizio
Goeman, Frauke
Melucci, Elisa
Biffoni, Mauro
Ricci-Vitiani, Lucia
UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title_full UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title_fullStr UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title_full_unstemmed UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title_short UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response
title_sort ucn-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing dna damage response
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190083/
https://www.ncbi.nlm.nih.gov/pubmed/27286453
http://dx.doi.org/10.18632/oncotarget.9859
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