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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)11332-11348
Number of pages17
JournalOncotarget
Volume7
Issue number10
DOIs
Publication statusPublished - 2016

Fingerprint

Histone Acetyltransferases
Neoplastic Stem Cells
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Cell Line
Neoplasms
Acetylation
Growth
Cell Survival
Thiazoles
Tubulin
Heterografts
Therapeutics
Apoptosis

Keywords

  • Acetylation
  • Apoptosis
  • Cancer stem cells
  • HAT inhibitors
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells. / Di Martile, Marta; Desideri, Marianna; De Luca, Teresa; Gabellini, Chiara; Buglioni, Simonetta; Eramo, Adriana; Sette, Giovanni; Milella, Michele; Rotili, Dante; Mai, Antonello; Carradori, Simone; Secci, Daniela; De Maria, Ruggero; Del Bufalo, Donatella; Trisciuoglio, Daniela.

In: Oncotarget, Vol. 7, No. 10, 2016, p. 11332-11348.

Research output: Contribution to journalArticle

Di Martile, M, Desideri, M, De Luca, T, Gabellini, C, Buglioni, S, Eramo, A, Sette, G, Milella, M, Rotili, D, Mai, A, Carradori, S, Secci, D, De Maria, R, Del Bufalo, D & Trisciuoglio, D 2016, 'Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells', Oncotarget, vol. 7, no. 10, pp. 11332-11348. https://doi.org/10.18632/oncotarget.7238
Di Martile, Marta ; Desideri, Marianna ; De Luca, Teresa ; Gabellini, Chiara ; Buglioni, Simonetta ; Eramo, Adriana ; Sette, Giovanni ; Milella, Michele ; Rotili, Dante ; Mai, Antonello ; Carradori, Simone ; Secci, Daniela ; De Maria, Ruggero ; Del Bufalo, Donatella ; Trisciuoglio, Daniela. / Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells. In: Oncotarget. 2016 ; Vol. 7, No. 10. pp. 11332-11348.
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AU - Sette, Giovanni

AU - Milella, Michele

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