A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone

Chimenti, Franco; Bizzarri, Bruna; Maccioni, Elias; Secci, Daniela; Bolasco, Adriana; Chimenti, Paola; Fioravanti, Rossella; Granese, Arianna; Carradori, Simone; Tosi, Federica; Ballario, Paola; Vernarecci, Stefano; Filetici, Patrizia

doi:10.1021/jm800885d

Cited by 109 publications

(76 citation statements)

References 52 publications

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“…Several epigenetic inhibitors have been developed and shown to induce differentiation, growth arrest, or apoptosis in tumor cells [7][8][9][10][39][40][41]. Among them, we previously characterized the thiazole derivative CPTH6, as a novel HAT inhibitor that activates the apoptotic program and modulates the autophagic flux in human tumor cell lines [11,12].…”

Section: Discussionmentioning

confidence: 99%

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

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

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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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Section: Discussionmentioning

confidence: 99%

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

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

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“…4F). Because histone acetyltransferases (HATs) have previously been reported to acetylate NF-kB (23), we next determined whether blocking HATs with the HAT inhibitor (HATi) AA (44)(45)(46) could diminish K310 acetylation in SCRIPT-KD-DCs. As shown in Fig.…”

Section: Dc-script Knockdown Leads To More K310 Acetylation Of Nf-kbp65mentioning

confidence: 99%

“…In addition to the broad specificity HATi AA (44)(45)(46), we also included the p300/ CBP-specific HATi's curcumin (47,48) and C646 (49) because p300/CBP has previously been implicated in NF-kB acetylation (23). As shown in Fig.…”

Section: Il-10 Production From Script-kd-dcs Depends On P300/cbpmentioning

confidence: 99%

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Søndergaard

Poghosyan

Hontelez

et al. 2015

The Journal of Immunology

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The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.

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“…Transduced cells were sorted for green fluorescence (FACS Aria; Becton Dickinson) Reagents preparation and treatment CPTH6 (3-methylcyclopentylidene-[4-(4 0 -chlorophenyl)thiazol-2-yl]hydrazone; Supplementary Fig. S1A) was synthesized as previously reported (24), dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich) at the concentration of 100 mmol/L and diluted to the final concentrations in complete medium. For all the experiments, cells were treated with 1% DMSO as control.…”

Section: Generation Of Bcl-2 Bcl-xl and Cflip Stably Overexpressingmentioning

confidence: 99%

“…Among them, several compounds have been described to elicit antiproliferative, proapoptotic, antitumoral, and antiangiogenic activity toward different tumor histotypes, and they may represent new therapeutic agents for cancer treatment and prevention (20)(21)(22)(23). Recently, a set of newly synthesized molecules derived from thiazole has been selected as modulators of the HATs in yeast-based drug screening (24). Among these compounds, the thiazole derivative CPTH6 has been chosen to evaluate its possible antitumoral activity in a large panel of leukemic and solid tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

CPTH6, a Thiazole Derivative, Induces Histone Hypoacetylation and Apoptosis in Human Leukemia Cells

Trisciuoglio

Ragazzoni

Pelosi

et al. 2012

Clinical Cancer Research

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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 0 -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 HAT activity. Moreover, it inhibits H3/H4 histones and a-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.

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A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone

Cited by 109 publications

References 52 publications

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

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

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

CPTH6, a Thiazole Derivative, Induces Histone Hypoacetylation and Apoptosis in Human Leukemia Cells

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