CPTH6, a thiazole derivative, induces histone hypoacetylation and apoptosis in human leukemia cells

Daniela Trisciuoglio, Ylenia Ragazzoni, Andrea Pelosi, Marianna Desideri, Simone Carradori, Chiara Gabellini, Giovanna Maresca, Riccardo Nescatelli, Daniela Secci, Adriana Bolasco, Bruna Bizzarri, Chiara Cavaliere, Igea D'Agnano, Patrizia Filetici, Lucia Ricci-Vitiani, Maria Giulia Rizzo, Donatella Del Bufalo

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Purpose: We previously identified novel thiazole derivatives able to reduce histone acetylation and histone acetyltransferase (HAT) activity in yeast. Among these compounds, 3-methylcyclopentylidene- [4-(4′-chlorophenyl) thiazol-2-yl]hydrazone (CPTH6) has been selected and used throughout this study. Experimental Design: The effect of CPTH6 on histone acetylation, cell viability and differentiation, cellcycle distribution, and apoptosis in a panel of acute myeloid leukemia and solid tumor cell lines has been evaluated. Results: Here, we showed that CPTH6 leads to an inhibition of Gcn5 and pCAF HATactivity. Moreover, it inhibits H3/H4 histones and α-tubulin acetylation of a panel of leukemia cell lines. Concentration- and time-dependent inhibition of cell viability, paralleled by accumulation of cells in the G 0/G 1 phase and depletion from the S/G 2M phases, was observed. The role of mitochondrial pathway on CPTH6-induced apoptosis was shown, being a decrease of mitochondrial membrane potential and the release of cytochrome c, from mitochondria to cytosol, induced by CPTH6. Also the involvement of Bcl-2 and Bcl-xL on CPTH6- induced apoptosis was found after overexpression of the two proteins in leukemia cells. Solid tumor cell lines from several origins were shown to be differently sensitive to CPTH6 treatment in terms of cell viability, and a correlation between the inhibitory efficacy on H3/H4 histones acetylation and cytotoxicity was found. Differentiating effect on leukemia and neuroblastoma cell lines was also induced by CPTH6. Conclusions: These results make CPTH6 a suitable tool for discovery of molecular targets of HAT and, potentially, for the development of new anticancer therapies, which warrants further investigations.

Original languageEnglish
Pages (from-to)475-486
Number of pages12
JournalClinical Cancer Research
Issue number2
Publication statusPublished - Jan 15 2012

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Trisciuoglio, D., Ragazzoni, Y., Pelosi, A., Desideri, M., Carradori, S., Gabellini, C., Maresca, G., Nescatelli, R., Secci, D., Bolasco, A., Bizzarri, B., Cavaliere, C., D'Agnano, I., Filetici, P., Ricci-Vitiani, L., Rizzo, M. G., & Del Bufalo, D. (2012). CPTH6, a thiazole derivative, induces histone hypoacetylation and apoptosis in human leukemia cells. Clinical Cancer Research, 18(2), 475-486. https://doi.org/10.1158/1078-0432.CCR-11-0579