Histone Deacetylases Regulate Gonadotropin-Releasing Hormone I Gene Expression via Modulating Otx2-Driven Transcriptional Activity.

PLoS One. 2012;7(6):e39770

Authors: Gan L, Ni PY, Ge Y, Xiao YF, Sun CY, Deng L, Zhang W, Wu SS, Liu Y, Jiang W, Xin HB

Abstract
BACKGROUND: Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. CONCLUSIONS/SIGNIFICANCE: Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases.

PMID: 22761896 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22761896?dopt=Abstract

M344 HDAC Inhibitor molecular weight M344 HDAC Inhibitor price

Histone Deacetylases Regulate Gonadotropin-Releasing Hormone I Gene Expression via Modulating Otx2-Driven Transcriptional Activity.

PLoS One. 2012;7(6):e39770

Authors: Gan L, Ni PY, Ge Y, Xiao YF, Sun CY, Deng L, Zhang W, Wu SS, Liu Y, Jiang W, Xin HB

Abstract
BACKGROUND: Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. CONCLUSIONS/SIGNIFICANCE: Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases.

PMID: 22761896 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22761896?dopt=Abstract

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Isolation and functional characterization of peptide agonists of PTPRJ, a tyrosine phosphatase receptor endowed with tumor suppressor activity.

ACS Chem Biol. 2012 Jul 3;

Authors: Paduano F, Ortuso F, Campiglia P, Raso C, Iaccino E, Gaspari M, Gaudio E, Mangone G, Carotenuto A, Bilotta A, Narciso D, Palmieri C, Agosti V, Artese A, Gomez-Monterrey I, Sala M, Cuda G, Iuliano R, Perrotti N, Scala G, Viglietto G, Alcaro S, Croce CM, Novellino E, Fusco A, Trapasso F

Abstract
PTPRJ is a receptor-type protein tyrosine phosphatase whose expression is strongly reduced in the majority of investigated cancer cell lines and tumor specimens. PTPRJ negatively interferes with mitogenic signals originating from several oncogenic receptor tyrosine kinases, including HGFR, PDGFR, RET and VEGFR-2. Here we report the isolation and characterization of peptides from a random peptide phage display library that bind and activate PTPRJ. These agonist peptides, which are able to both circularize and form dimers in acqueous solution, were assayed for their biochemical and biological activity on both human cancer cells and primary endothelial cells (HeLa and HUVEC, respectively). Our results demonstrate that binding of PTPRJ-interacting peptides to cell cultures dramatically reduce the extent of both MAPK phosphorylation and total phosphotyrosine levels; conversely, they induce a significant increase of the cell cycle inhibitor p27Kip1. Moreover, PTPRJ agonist peptides both reduce proliferation and trigger apoptosis of treated cells. Our data indicate that peptide agonists of PTPRJ positively modulate the PTPRJ activity and may lead to novel targeted anticancer therapies.

PMID: 22759068 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22759068?dopt=Abstract

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Histone Deacetylase Inhibitors Facilitate Dihydroartemisinin-Induced Apoptosis in Liver Cancer In Vitro and In Vivo.

PLoS One. 2012;7(6):e39870

Authors: Zhang CZ, Pan Y, Cao Y, Lai PB, Liu L, Chen GG, Yun J

Abstract
Liver cancer ranks in prevalence and mortality among top five cancers worldwide. Accumulating interests have been focused in developing new strategies for liver cancer treatment. We have previously showed that dihydroartemisinin (DHA) exhibited antitumor activity towards liver cancer. In this study, we demonstrated that histone deacetylase inhibitors (HDACi) significantly augmented the antineoplastic effect of DHA via increasing apoptosis in vitro and in vivo. Inhibition of ERK phosphorylation contributed to DHA-induced apoptosis, due to the fact that inhibitor of ERK phosphorylation (PD98059) increased DHA-induced apoptosis. Compared with DHA alone, the combined treatment with DHA and HDACi reduced mitochondria membrane potential, released cytochrome c into cytoplasm, increased p53 and Bak, decreased Mcl-1 and p-ERK, activated caspase 3 and PARP, and induced apoptotic cells. Furthermore, we showed that HDACi pretreatment facilitated DHA-induced apoptosis. In Hep G2-xenograft carrying nude mice, the intraperitoneal injection of DHA and SAHA resulted in significant inhibition of xenograft tumors. Results of TUNEL and H&E staining showed more apoptosis induced by combined treatment. Immunohistochemistry data revealed the activation of PARP, and the decrease of Ki-67, p-ERK and Mcl-1. Taken together, our data suggest that the combination of HDACi and DHA offers an antitumor effect on liver cancer, and this combination treatment should be considered as a promising strategy for chemotherapy.

PMID: 22761917 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22761917?dopt=Abstract

M344 HDAC Inhibitor structure M344 HDAC Inhibitor solubility

Histone Deacetylase Inhibitors Facilitate Dihydroartemisinin-Induced Apoptosis in Liver Cancer In Vitro and In Vivo.

PLoS One. 2012;7(6):e39870

Authors: Zhang CZ, Pan Y, Cao Y, Lai PB, Liu L, Chen GG, Yun J

Abstract
Liver cancer ranks in prevalence and mortality among top five cancers worldwide. Accumulating interests have been focused in developing new strategies for liver cancer treatment. We have previously showed that dihydroartemisinin (DHA) exhibited antitumor activity towards liver cancer. In this study, we demonstrated that histone deacetylase inhibitors (HDACi) significantly augmented the antineoplastic effect of DHA via increasing apoptosis in vitro and in vivo. Inhibition of ERK phosphorylation contributed to DHA-induced apoptosis, due to the fact that inhibitor of ERK phosphorylation (PD98059) increased DHA-induced apoptosis. Compared with DHA alone, the combined treatment with DHA and HDACi reduced mitochondria membrane potential, released cytochrome c into cytoplasm, increased p53 and Bak, decreased Mcl-1 and p-ERK, activated caspase 3 and PARP, and induced apoptotic cells. Furthermore, we showed that HDACi pretreatment facilitated DHA-induced apoptosis. In Hep G2-xenograft carrying nude mice, the intraperitoneal injection of DHA and SAHA resulted in significant inhibition of xenograft tumors. Results of TUNEL and H&E staining showed more apoptosis induced by combined treatment. Immunohistochemistry data revealed the activation of PARP, and the decrease of Ki-67, p-ERK and Mcl-1. Taken together, our data suggest that the combination of HDACi and DHA offers an antitumor effect on liver cancer, and this combination treatment should be considered as a promising strategy for chemotherapy.

PMID: 22761917 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22761917?dopt=Abstract

m344 Learn here

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

M344 HDAC Inhibitor molecular weight M344 HDAC Inhibitor price

Prostate, we have KW-2478 the F ll Evaluation of acute retention Urinary and prostate surgery, according to the peri five months. Associated current procedural terminology codes and ICD 9 cm for the clinical outcomes of interest are listed in Table 1. We also examined the pharmacy and medical costs associated with BPH. The co-operation Ts were as those Subject GE, which is defined on a loan account. Medical costs were specific to BPH than those associated with medical claims with a primary Ren diagnosis of BPH and all claims with a CPT code is defined by interest. Claims with re U with acute urinary retention diagnosed a d be accompanied by a specific code corresponding to BPH. We examined the medical costs during the month trial period in September and the results discussed in common Ts may need during the pharmacy 12 months follow-up period.
Assessed with this method k Nnten we Konomische analysis, the progressive Ver Change in the medical costs that may be affected by 5 IRA and Co k Ts total values in connection with the use of five IRA. The patient KSP inhibitor in clinical trials k Can medical expenses may need during the period of five months caused death, including medical expenses in connection BPH. There was the purpose of our analysis, however, to evaluate the effect of five IRA on the clinical results and the collaboration TS relatives, we have not assessed the cooperation Ts associated with acute urinary retention and prostate surgery, and these drugs should be clinically effective.7, 8 We examined differences in baseline covariates for all cohorts treated with the t-test when data were continuous in nature and using a chi-square test if the data were categorical.
We evaluated the probability of clinical progression, acute urinary retention and prostate surgery related using logistic regression, as a function of treatment MLN518 cohorts modeled, and pre-index covariates: age, presence of acute retention Urine, BPH stage Charlson Komorbidit t index, the number of unique diagnosis codes, the number of individual drugs, H Maturie requirements, Blasenfunktionsst, Incontinence and bladder stones. To evaluate the stage BPH, we assign each patient to one of the seven stages of disease severity to the Thomson Medstat disease staging system, 13 based on the presence of ICD-9 inch six months before the survey deadline.
Thomson is the method for encoding an exclusively Lichen criterion is in big em Ma E are used to diagnostic categories and to classify severity of the disease. The system detects all m Resembled diseases and have different degrees of severity of each disease on diagnosis codes and procedures that the patient is suffering based. For BPH, the codes in the first place for the assessment of the presence of complications such as obstruction of the bladder, hydronephrosis, renal failure, sepsis or shock. We used a generalized linear model with a log link function Hnlichen covariates on differences in the co-evaluated Medical ts. We performed all statistical analyzes using SAS version 9.1.3 with an a priori significance the 0.05. All Co Ts have been adjusted to 2008 dollars per year, based on the medical care component of the index of consumer prices, and have been co Ts per patient presented. A total of 8.617 patients were plated in the database market scan 64.5% in the early treatment cohort and 35.5% in the cohort Siege therapy identified. Initially, the patients in the first cohort of more Komorbidit Th,

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

Find more M344 HDAC Inhibitors 251456-60-7

Cancer you invited two large clinical studies to investigate the e r m resembled the 5AR inhibitors in the prevention of prostate cancer Pr: The Prostate Cancer Prevention Trial and the reduction of dutasteride of prostate cancer events. The CPP was a multicenter, randomized, double-blind, controlled clinical trial against placebo TKI258 Dovitinib Fi nasteride compared with placebo in the prevention of prostate adenocarcinoma. 18 882 M Men over 55 with a PSA of 3.0 ng / ml or less and a normal DRE at age were randomized to receive seven years nasteride fi t Possible or placebo. The study participants were measured with a J Hrlichen PSA and digital rectal examination followed. TRUS-guided biopsies were performed for gr He performed than or equal to 4 ng / ml PSA or abnormal DRE.
In addition, all M Men for biopsy study end after seven years of treatment recommended are passed. Included among the 9060 M Nnern in the statistical analysis of internal fi, 18.4% of the men in the group fi nasteride with adenocarcinoma of the prostate were diagnosed, compared with 24.4% in the placebo group, a lower risk of 24.8%. A significant difference was analyzed in all subgroups, and about 98% of cancers in both groups were organized, denied the trust. Despite the drastic reduction in the risk of 24.8% compared to the diagnosis of prostate cancer in the PCPT study population, different topics to a broad acceptance of the fi nasteride as a preventive treatment for prostate cancer have been prevented. Zun Highest nasteride if the treatment was poor with an increased Hten rate of diagnosis of prostate cancer associated differentiated from placebo.
In addition, rates of prostate cancer diagnosis much h Ago were as expected in both study groups. Closing Lich, almost half of the H All positive diagnoses of cancer in the study were biopsies, tumors with a clinically significant EndOf Cancer is unknown. The PPC has had with immediate skepticism from some researchers and clinicians, from fears that fi nasteride weight Hlt and accelerates the growth of high-grade tumors fueled fulfilled. The subsequent Analysis of the PCPT data provide an alternative hypothesis, which is slightly h Recognized herer percentage of high-grade tumors in the treatment group explained Ren. Rst Of the green was-Run difference in the proportion of cancers of high or low quality T between treatment and placebo groups demonstrated in these subjects w Observed during biopsies for cause, such as biopsies to study to find.
The hazard ratio for the detection of prostate cancer degrees in of the treated group erh Ht themselves not w During of the clinical study to erh hen. In fact, the number of the men with prostate cancer with high w During the end-point biopsies diagnosed Similar in both study groups. The subsequent End analysis showed that fi nasteride infl uence the properties of the PSA as a screening test, which increased its sensitivity Ht in all types of prostate cancer in general and the high quality t prostate cancer in particular. In addition, the PSA is more sensitive for prostate cancer in high-quality cut-off PSA levels between 1.1 ng / ml to 10.1 ng / ml, which reduced the rate of false negative and increased The rate of diagnosis of high grade tumors hen . Is why assumes the combination of cancer-Chemopr Vention, the lowering of the PSA and PSA sensitivity for the gro Ec

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

More information m344