Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells
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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
Daniela Trisciuoglio, e-mail: email@example.com
Donatella Del Bufalo, e-mail: firstname.lastname@example.org
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.
Marta Di Martile
Primary Contact _
Teresa De Luca
Ruggero De Maria
Donatella Del Bufalo
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