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

Michele Signore, Mariachiara Buccarelli, Emanuela Pilozzi, Gabriele De Luca, Marianna Cappellari, Maurizio Fanciulli, Frauke Inger Karen Goeman, Elisa Melucci, Mauro Biffoni, Lucia Ricci-Vitiani

Research output: Contribution to journalArticle

Abstract

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 phosphoproteomic 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.

Original languageEnglish
Pages (from-to)44113-44128
Number of pages16
JournalOncotarget
Volume7
Issue number28
DOIs
Publication statusPublished - 2016

Keywords

  • Chk1
  • Colorectal cancer stem-like cells
  • DNA damage
  • Kinase inhibitors
  • Phospho-proteomics

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Signore, M., Buccarelli, M., Pilozzi, E., De Luca, G., Cappellari, M., Fanciulli, M., Goeman, F. I. K., Melucci, E., Biffoni, M., & Ricci-Vitiani, L. (2016). UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response. Oncotarget, 7(28), 44113-44128. https://doi.org/10.18632/oncotarget.9859