Research Papers:

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Marta Di Martile _, Marianna Desideri, Teresa De Luca, Chiara Gabellini, Simonetta Buglioni, Adriana Eramo, Giovanni Sette, Michele Milella, Dante Rotili, Antonello Mai, Simone Carradori, Daniela Secci, Ruggero De Maria, Donatella Del Bufalo, Daniela Trisciuoglio

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Oncotarget. 2016; 7:11332-11348. https://doi.org/10.18632/oncotarget.7238

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Marta Di Martile1, Marianna Desideri1, Teresa De Luca1, Chiara Gabellini1, Simonetta Buglioni1, Adriana Eramo2, Giovanni Sette2, Michele Milella3, Dante Rotili4, Antonello Mai4,5, Simone Carradori4, Daniela Secci4, Ruggero De Maria6, Donatella Del Bufalo1, Daniela Trisciuoglio1

1Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy

2Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

3Clinical and Experimental Oncology Department, Regina Elena National Cancer Institute, Rome, Italy

4Department of Drug Chemistry and Technologies, ‘Sapienza’ University, Rome, Italy

5Pasteur Institute, Cenci Bolognetti Foundation, ‘Sapienza’ University, Rome, Italy

6Scientific Director, Regina Elena National Cancer Institute, Rome, Italy

Correspondence to:

Daniela Trisciuoglio, e-mail: trisciuoglio@ifo.it

Donatella Del Bufalo, e-mail: delbufalo@ifo.it

Keywords: HAT inhibitors, cancer stem cells, acetylation, apoptosis, non-small cell lung cancer

Received: September 08, 2015    Accepted: January 23, 2016    Published: February 08, 2016


Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4’-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.

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