title: CPTH6, a thiazole derivative, induces histone hypoacetylation and apoptosis in human leukemia cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The effect of CPTH6 on histone acetylation, cell viability and differentiation, cell-cycle 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 HAT activity. 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(2)M 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.
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. delbufalo@ifo.it
authors: Daniela
authors: D
authors: Trisciuoglio
authors: Ylenia
authors: Y
authors: Ragazzoni
authors: Andrea
authors: A
authors: Pelosi
authors: Marianna
authors: M
authors: Desideri
authors: Simone
authors: S
authors: Carradori
authors: Chiara
authors: C
authors: Gabellini
authors: Giovanna
authors: G
authors: Maresca
authors: Riccardo
authors: R
authors: Nescatelli
authors: Daniela
authors: D
authors: Secci
authors: Adriana
authors: A
authors: Bolasco
authors: Bruna
authors: B
authors: Bizzarri
authors: Chiara
authors: C
authors: Cavaliere
authors: Igea
authors: I
authors: D'Agnano
authors: Patrizia
authors: P
authors: Filetici
authors: Lucia
authors: L
authors: Ricci-Vitiani
authors: Maria Giulia
authors: MG
authors: Rizzo
authors: Donatella
authors: D
authors: Del Bufalo
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D051379:Mice; D009447:Neuroblastoma; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D006657:Histones; D013844:Thiazoles; D014404:Tubulin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C573972:3-methylcyclopentylidene-(4-(4'-chlorophenyl)thiazol-2-yl)hydrazone