Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.

Oral Oncol. 2012 Jun 27;

Authors: Haigentz M, Kim M, Sarta C, Lin J, Keresztes RS, Culliney B, Gaba AG, Smith RV, Shapiro GI, Chirieac LR, Mariadason JM, Belbin TJ, Greally JM, Wright JJ, Haddad RI

Abstract
OBJECTIVES: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. METHODS: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13mg/m(2) as a 4-h intravenous infusion on days 1, 8 and 15 of 28day cycles, with response assessment by RECIST every 8weeks. RESULTS: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. CONCLUSIONS: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

PMID: 22748449 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22748449?dopt=Abstract

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Anti-breast Cancer Effects of Histone Deacetylase Inhibitors and Calpain Inhibitor.

Anticancer Res. 2012 Jul;32(7):2523-9

Authors: Mataga MA, Rosenthal S, Heerboth S, Devalapalli A, Kokolus S, Evans LR, Longacre M, Housman G, Sarkar S

Abstract
Development of new breast cancer therapies is needed, particularly as cells become refractory or develop increased drug resistance. In an effort to develop such treatments, class I and II histone deacetylases (HDACs), alone and in combination with other cytotoxic agents, are currently in clinical trial. Herein, we discuss the effects of histone deacetylase inhibitors (HDACi) when used in combination with calpeptin, an inhibitor of the regulatory protease, calpain. We present results of study in two breast cancer cells lines with distinct characteristics: MDA-MB-231 and MCF-7. When used in combination with calpeptin, two chemically distinct HDACi significantly inhibited growth and increased cell death by inducing cell-cycle arrest and apoptosis. MCF-7 cells exhibited a greater proportion of arrest at the G(1) phase, whereas triple-negative MDA-MB-231 cells exhibited increased cell cycle arrest at the S phase. Methylation of the imprinted and silenced proapoptoic tumor suppressor gene aplasia Ras homolog member I (ARHI) was reduced in both cell lines after treatment with HDACi. However, it was only re-expressed on such treatment in MDA-MB-231 cells, suggesting that re-expression operates under differential mechanisms in these two cell lines. Collectively, these results showed that the combination of HDACi and calpeptin inhibited the growth of two distinctly different types of breast cancer cells and could have wide clinical applications, though the mechanisms of inhibition are possibly different.

PMID: 22753709 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22753709?dopt=Abstract

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Synergistic Killing of Glioblastoma Stem-like Cells by Bortezomib and HDAC Inhibitors.

Anticancer Res. 2012 Jul;32(7):2407-13

Authors: Asklund T, Kvarnbrink S, Holmlund C, Wibom C, Bergenheim T, Henriksson R, Hedman H

Abstract
BACKGROUND: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge.
MATERIALS AND METHODS: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy.
RESULTS: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments.
CONCLUSION: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

PMID: 22753697 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22753697?dopt=Abstract

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Tooth-or p53-independent Ngigen apoptotic stimuli. In HCT116 but not HT 29 cells, CPT treatment 11 significantly induces the expression of Bax and Noxa also compared to the vehicle-treated cells regulated. We have also found that 38 SN-regulated Noxa expression increased BI6727 Volasertib in HCT116 cells. Given the induction of Noxa by CPT-11 in HCT116 cells, we have the effect of the drug Sen treatment on the interaction between Noxa and Mcl high affinity t partners to Noxa / MCL-1 complex. To resolve this problem, immunpr Zipitiert we probed for Noxa and Mcl 1 in HCT116 cells treated with CPT-11 or vehicle. 11 CPT treatment has been shown to improve the interaction of Noxa and Mcl first It was suggested that the regulation of Noxa k Bak can activate the shift Mcl of an ant.
In this model, treatment with CPT-11 Bergenin inhibitor is shown to Bak from its interaction with MCL 1 l Sen. Although a previous study suggested that Mcl binding of F Is k Rpereigene Noxa induced by the F Ability, a sequester Mcl Bim st Ren can k, 11 failed CPT treatment, show a significant effect on Mcl complex 1 and Bim. Taken together, the induction of Noxa by CPT 11 Mcl sequester 1 and Bak also free of Mcl 1, which can to enhance the apoptotic effect of CPT 11 and ABT 737 contribute combination k. Knockdown of Noxa d mpft The cytotoxicity t of CPT 11 plus ABT 737 To further the importance of Noxa Regulation show as an m Glicher mechanism for the synergistic cytotoxicity t of CPT 11 and ABT 737, we generated knockdown Noxa HCT116 cells with lentiviral shRNA delivery. Knockdown of Noxa found to significantly reduce the sensitivity to CPT-11 plus ABT 737, as shown using two shRNA constructs.
In addition, blocked removable Noxa the activation of caspase 3 induced by the combination of drugs. 11 Because CPT does not induce Noxa in HT 29 cells, we generated Noxa knockdown HT 29 cells. Knockdown Noxa had no effect on HT 29 cells sensitive to the combination of ABT 737 and CPT 11, although a slight protection at a dose of 10 μ ABT 737 mol / L was observed was at a dose of 10 μ mol / L ABT showed 737 to induce Noxa weak. Together, these data show that Noxa is an important regulator of apoptosis sensitivity to this drug combination. To show that the induction of Noxa is an important mechanism to improve the sensitivity to increased Hen apoptotic repr Presents, we used the proteasome inhibitor bortezomib has been shown that Noxa to induce myeloma cells, human cells of mantle cell lymphoma, and non-small cell lung cancer.
Treatment of HCT116 and HT-29 cell lines with bortezomib was shown to significantly induce Noxa in both cell lines. Co-administration of ABT 737 and bortezomib has been shown that the cleavage of caspases and enhance cytotoxicity of t in both cell lines in a green Eren Ausma compared to either drug alone. With Noxa knockdown HCT116 and HT 29 cells, we observed that Noxa shRNA cells from caspase 3 cleavage and cytotoxicity t of bortezomib and ABT 737 induced protection. We also found that 11 CPT Noxa induce in another cell line of c Lon, RKO, a high Ma expressed on Mcl first In these cells, ABT 737 again demonstrated that CPT cytotoxicity t 11 and extend cleavage of caspases. These data suggest that our results can be generalized k To other cancer cell lines of c Lon. ABT 737 is discussed

Transient, nucleons calcineurin Ren factor of activated T-cells and A1 resistance h Depends ABT 737 to antigen recognition. The calcineurin inhibitor CsA blocked and prevented up-regulation of A1 resistance to ABT 737 in activated T cells, providing new M Opportunities for effective combination therapies. Results Activated T-cells are resistant to ABT 737th To investigate LY2228820 the effects of allogeneic T-cell activation on the sensitivity to Bcl-2 inhibitor ABT-737, we used the BM3 transgenic mouse strain.

3, all the CD8 T-cell is a transgenic TCR specific for class I Haupthistokompatibilit Tskomplex H 2 molecule can be KB and the clonotypic Antique Detected body Ti98 suppressed. In the first experiment, we transplanted BM3. 3 bone marrow into irradiated Mice CBA non fa If t Harmful for Mice, the synchimeric to bring BM3 expression.
3 TCR only over a fraction of the pool-type CD8 These well-defined Aromatase Enzyme homogeneous population alloreactive CD8 T cells k Can then w Follow during a HVG reaction in connection with a physiological immune system in different ways. Synchimeras re U donor-specific transfusion and treatment with either 737 or ABT vehicle, starting 2 days after the summer. On day 5 after amor Age showed Mice that were treated with ABT 737, a 75% reduction of T cells in peripheral blood CD4 and CD8 T cells were also affected by the treatment. After antigen recognition, the percentage of cells Ti98t between CD8 T cells in both groups increased Ht, but this effect significantly in the ABT 737 in improved compared to the control.
This observation by a variety of activated cells Ti98t between CD8 T cells under the effect of ABT 737 is explained Utert, whichmay by hom Be extended proliferation in lymphopenic environments ostatische. To limit the confounding effect of hom Ostatische proliferation, we conducted a Hnliches experiment in a model of GVHD. The combination of a parent to F1 model with the BM3. Three transgenic system allows us to target a homogeneous population of host-reactive CD8 T cells in the absence of rejection by analyzing the receiver singer and without the effects of conditioning that the immune response and regulation VER Can change k, Apoptosis. We minimize the effect of T cell proliferation by the choice of a short protocol: BM3. 3 splenocytes were transferred to adoptive or ABC F1 receiver singer.
Started on day 1 after treatment with ABT 737 transmission or the vehicle was, and two days later Ter, receiver singer-Mice were removed for analysis by fluorescence-activated cell sorting get Tet. ABT 737 mini-cell activation influences Ti98t and even reduced the number of total splenocytes in F1 and CBA receiver singer for about 30% discount. In the syngeneic combination, cells were also Ti98t that Ngern the entire T-lymphocytes, and total splenocytes, w While at receiver Of F1 donor cells alloactivated CD8tTi98t reagents reduced resistance to ABT 737th Consequently, the total number of cells in the receiver Ngern Ti98t CBA was significantly reduced after treatment with ABT 737, but no difference in the total number of cells Ti98t between the two groups was recorded after allogeneic stimulation. These data suggest that had the resistance of activated T cells to ABT-737 Ti98t developed in both experiments and HVG GVHD. This hypothesis was tested in vitro in a mixed lymphocyte culture

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LBH589 enhances T-cell activation in vivo and accelerates graft-versus-host disease in mice.

Biol Blood Marrow Transplant. 2012 Jun 11;

Authors: Wang D, Iclozan C, Liu C, Xia C, Anasetti C, Yu XZ

Abstract
Histone deacetylase inhibitors (HDACi) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The FDA approved HDACi, Vorinostat or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of pro-inflammatory cytokines. In preclinical allogeneic transplantation models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia (GVL). LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplantation (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T-cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT, and alerts that LBH589 (Panobinostat) could have adverse effect on GVHD, and possibly on other inflammatory diseases.

PMID: 22698484 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22698484?dopt=Abstract

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Role for Class I histone deacetylases in multidrug resistance.

Exp Cell Res. 2012 Feb 1;318(3):177-86

Authors: Xu Y, Jiang Z, Yin P, Li Q, Liu J

Abstract
Recent reports have showed that histone deacetylase (HDAC) inhibitor resulted in multidrug resistance (MDR) to other chemotherapeutic agents. However, the molecular mechanisms of Class I HDACs on MDR regulation are poorly understood. In this study, HDAC1 and HDAC2 acted as enhancers to intensify the chemosensitivities of anti-cancer drugs via reducing the expression levels of P-gp, MRP1 and MRP2. Furthermore, the dissociation of HDAC1 and HDAC2 led to transcriptional regulation of P-gp expression via the recruitment of p300, PCAF and NF-Y to the P-gp promoter region, which subsequently increased the level of the active gene marker, hyperacetylated histone H3. In parallel, selective inhibition of HDAC1 and HDAC2 induced the recruitment of p300, PCAF, NF-Y via acetylation of Sp1. Thus, our findings showed HDAC1 and 2 regulated P-gp expression through dynamic changes in chromatin structure and transcription factor association within the promoter region.

PMID: 22154511 [PubMed - indexed for MEDLINE]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22154511?dopt=Abstract

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Aromatic polyketide production in Cordyceps indigotica, an entomopathogenic fungus, induced by exposure to a histone deacetylase inhibitor.

Org Lett. 2012 Apr 20;14(8):2006-9

Authors: Asai T, Yamamoto T, Oshima Y

Abstract
Cultivation of Cordyceps indigotica, an entomopathogenic fungus, in the presence of suberoyl bis-hydroxamic acid (an HDAC inhibitor) greatly activated its polyketide synthesis apparatus to afford six novel aromatic polyketides, indigotides C-F (1-4), 13-hydroxyindigotide A (5), and 8-O-methylindigotide B (6). The structures of these compounds were determined by NMR spectroscopic analyses. Among the compounds, indigotides C-E (1-3) possessed unprecedented dimeric polyketide frameworks possibly generated via a [4 + 2] cycloaddition or Michael type reaction.

PMID: 22480311 [PubMed - indexed for MEDLINE]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22480311?dopt=Abstract

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Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene.

J Psychiatr Res. 2012 May;46(5):635-43

Authors: Fujita Y, Morinobu S, Takei S, Fuchikami M, Matsumoto T, Yamamoto S, Yamawaki S

Abstract
Histone acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitates fear extinction, using a contextual fear conditioning (FC) paradigm, in Sprague-Dawley rats. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone H3 and H4 were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR) and protein by Western blotting. 2 h after vorinostat administration, the levels acetylated histones and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus. The NR2B protein level was elevated 4 h after vorinostat administration. Last, we investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The ChIP assay revealed increases in the levels of acetylated histones and they were accompanied by enhanced binding of p-CREB to its binding site at the promoter of the NR2B gene 2 h after vorinostat administration. These findings suggest that vorinostat increases the expression of NR2B in the hippocampus by enhancing histone acetylation, and this process may be implicated in fear extinction.

PMID: 22364833 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22364833?dopt=Abstract

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Ritonavir interacts with bortezomib to enhance protein ubiquitination and histone acetylation synergistically in renal cancer cells.

Urology. 2012 Apr;79(4):966.e13-21

Authors: Sato A, Asano T, Ito K, Asano T

Abstract
OBJECTIVE: To investigate the combined effects of the HIV protease inhibitor ritonavir and proteasome inhibitor bortezomib on renal cancer cells. Ritonavir induces endoplasmic reticulum (ER) stress and we hypothesized that inhibiting proteasome activity under ER stress would further inhibit cancer cell growth by enhancing protein ubiquitination.
METHODS: The effectiveness of the combination of ritonavir and bortezomib on renal cancer cells (Caki-1, ACHN, 786-O, 769-P) was assessed by MTS assay, colony formation assay, cell cycle analysis, and annexin-V assay. In vivo efficacy was evaluated using mice subcutaneous tumor models. Induction of ER stress, protein ubiquitination, histone acetylation, and changes in the expression of histone deacetylase (HDAC) were evaluated by Western blotting.
RESULTS: Ritonavir in combination with bortezomib induced apoptosis and inhibited renal cancer growth synergistically at clinically feasible concentrations. In subcutaneous tumor models using Caki-1 cells, 10-day treatment with the combination was well tolerated and inhibited tumor growth significantly. Ritonavir induced ER stress and the combination enhanced protein ubiquitination synergistically. The combination was also found to induce histone acetylation by suppressing the HDAC expression.
CONCLUSION: The combination of ritonavir and bortezomib inhibits renal cancer growth synergistically. The effectiveness of the combination is caused by protein ubiquitination and histone acetylation. Our results provide a rationale for investigating the combination in patients with renal cancer.

PMID: 22296623 [PubMed - indexed for MEDLINE]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22296623?dopt=Abstract

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