5-alpha-reductase: 2012-07-01

2012年7月7日星期六

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.

Nature. 2012 Jul 1;

Authors: Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, Steinberg J, Crawley JN, Regehr WG, Sahin M

Abstract
Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

PMID: 22763451 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22763451?dopt=Abstract

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Comparative Study of Rapamycin and Temsirolimus Demonstrates Superimposable Anti-Tumour Potency on Prostate Cancer Cells.

Comparative Study of Rapamycin and Temsirolimus Demonstrates Superimposable Anti-Tumour Potency on Prostate Cancer Cells.

Basic Clin Pharmacol Toxicol. 2012 Jul 4;

Authors: Fagone P, Donia M, Mangano K, Quattrocchi C, Mammana S, Coco M, Libra M, McCubrey JA, Nicoletti F

Abstract
Rapamycin is a macrocyclic lactone currently used for the treatment of cancer and for the prevention of transplant rejection. The primary pharmacological mode of action of rapamycin occurs through the inhibition (blocking) of the mammalian target of rapamycin (mTOR). By doing so, rapamycin interferes with the phosphoinositide 3-kinase (PI3K)-Akt-mTOR axis that controls several cellular functions involving cell growth, proliferation and angiogenesis. The frequent activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in advanced prostate cancer has provided a rationale for the use of mTOR inhibitors in this setting. We carried out a comparative study on the effects of rapamycin and temsirolimus on the in vitro and in vivo growth of the prostate cancer cell lines, LnCap and PC3. Our results demonstrate that rapamycin and temsirolimus exert similar in vitro and in vivo anti-proliferative effects against prostate cancer cells.

PMID: 22762560 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22762560?dopt=Abstract

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Antitumor efficacy of sequential treatment with docetaxel and 5-fluorouracil against human oral cancer cells.

Antitumor efficacy of sequential treatment with docetaxel and 5-fluorouracil against human oral cancer cells.

Int J Oncol. 2012 Jul 4;

Authors: Tamatani T, Ferdous T, Takamaru N, Hara K, Kinouchi M, Kuribayashi N, Ohe G, Uchida D, Nagai H, Fujisawa K, Miyamoto Y

Abstract
Docetaxel (DOC) and 5-fluorouracil (5-FU) are important anticancer agents widely used in the treatment of a variety of cancers including oral squamous cell carcinomaÂ (OSCC). The purpose of this study was to determine the antitumor efficacy of the sequential administration of DOC and 5-FU against OSCC cells (B88 and CAL27 cells) inÂ vitro and inÂ vivo. In inÂ vitro growth inhibition assays, sequential treatment with DOC followed by 5-FU was more effective in inhibiting cancer cell growth than 5-FU followed by DOC, single treatment with DOC or 5-FU, or combined treatment with DOC and 5-FU. Furthermore, DOC followed by 5-FU significantly inhibited tumor growth inÂ vivo compared to 5-FU followed by DOC. To understand the mechanisms underlying the enhanced growth inhibitory effect of the administration sequence, DOC followed by 5-FU, we examined the expression of 5-FU metabolic enzymes such as thymidylate synthaseÂ (TS), dihydropyrimidine dehydrogenaseÂ (DPD) and orotate phosphoribosyl transferaseÂ (OPRT), which were known to regulate the antitumor effect of 5-FU, by real-time RT-PCR and western blot analysis. Downregulation of TS and DPD expression and upregulation of OPRT expression were induced by DOC treatment, suggesting that DOC enhanced the efficacy of 5-FU by altering the expression of its metabolic enzymes. These results indicate that sequential treatment with DOC followed by 5-FU could be a promising therapeutic strategy for oral cancer.

PMID: 22766915 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22766915?dopt=Abstract

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TORC1 of fission yeast is rapamycin-sensitive.

TORC1 of fission yeast is rapamycin-sensitive.

Genes Cells. 2012 Jul 5;

Authors: Takahara T, Maeda T

Abstract
The target of rapamycin (TOR) protein kinase plays central roles in the regulation of cell growth in response to nutritional availability. TOR forms two distinct multiprotein complexes termed TOR complex 1 (TORC1) and TORC2. Typically, only the activity of TORC1 is inhibited by the immunosuppressant rapamycin. Although rapamycin strongly inhibits cell growth of the budding yeast Saccharomyces cerevisiae through inhibition of TORC1, growth of the fission yeast Schizosaccharomyces pombe appears to be resistant to rapamycin. Here, we demonstrate that rapamycin inhibits the kinase activity of S.Â pombe TORC1 in vitro in a similar manner to TORC1 of other organisms. We furthermore show that incomplete inhibition of TORC1 by rapamycin underlies the apparent rapamycin resistance of S.Â pombe. In the presence of caffeine, which potentially lowers TORC1 activity, the growth of wild-type S.Â pombe cells is sensitive to rapamycin in a TORC1-dependent manner. Moreover, treatment of S.Â pombe cells with rapamycin plus caffeine induces starvation-specific gene expression and autophagy, similarly to cells with reduced TORC1 activity. These results indicate that rapamycin does inhibit TORC1 in S.Â pombe, but the inhibition is not sufficient to cause a growth defect. These findings establish a universal action of rapamycin on TORC1 inhibition.

PMID: 22762302 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22762302?dopt=Abstract

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Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer.

Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer.

Invest New Drugs. 2012 Jul 3;

Authors: Manegold C, Vansteenkiste J, Cardenal F, Schuette W, Woll PJ, Ulsperger E, Kerber A, Eckmayr J, von Pawel J

Abstract
Introduction This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins Î±VÎ²3 and Î±VÎ²5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC). Methods Patients (nâ€‰=â€‰140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600Â mg/m(2) twice weekly, or docetaxel 75Â mg/m(2) once every 3Â weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1Â year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small. Results Median PFS was 54, 63, 63, and 67Â days for cilengitide 240, 400, and 600Â mg/m(2), and docetaxel 75Â mg/m(2), respectively. One-year survival rates were 13Â %, 13Â %, 29Â %, and 27Â %, respectively. The response rate (partial response only) with docetaxel was 15Â %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13Â % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients. Conclusion With the highest dose of cilengitide (600Â mg/m(2)), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75Â mg/m(2) and there were fewer grade 3/4 treatment-related adverse events.

PMID: 22752690 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22752690?dopt=Abstract

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2012年7月6日星期五

Stent elution rate determines drug deposition and receptor-mediated effects.

Stent elution rate determines drug deposition and receptor-mediated effects.

J Control Release. 2012 May 26;161(3):918-926

Authors: Tzafriri AR, Groothuis A, Price GS, Edelman ER

Abstract
Drug eluting stent designs abound and yet the dependence of efficacy on drug dose and elution duration remains unclear. We examined these issues within a mathematical framework of arterial drug distribution and receptor binding following stent elution. Model predictions that tissue content linearly tracks stent elution rate were validated in porcine coronary artery sirolimus-eluting stents implants. Arterial content varied for stent types, progressively declining from its Day 1 peak and tracking with rate-limiting drug elution - near zero-order release was three-fold more efficient at depositing drug in the stented lesion than near first-order release. In vivo data were consistent with an overabundance of non-specific sirolimus-binding sites relative to the specific receptors and to the delivered dose. The implication is that the persistence time of receptor saturation and effect is more sensitive to duration of elution than to eluted amount. Consequently, the eluted amount should be sufficiently high to saturate receptors at the target lesion, but dose escalation alone is an inefficient strategy for prolonging the duration of sirolimus deposition. Moreover, receptor saturating drug doses are predicted to be most efficacious when eluted from stents in a constant zero order fashion as this maximizes the duration of elution and receptor saturation.

PMID: 22642931 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22642931?dopt=Abstract

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Symptomatic abnormal vessel wall reaction after implantation of the first generation sirolimus-eluting stent: A case series.

Symptomatic abnormal vessel wall reaction after implantation of the first generation sirolimus-eluting stent: A case series.

Cardiovasc Revasc Med. 2012 May;13(3):196-200

Authors: Mostafa AE, Richardt G, Abdel-Wahab M

Abstract
AIMS: Expansive vessel wall remodeling has been previously reported after implantation of drug-eluting stents. These abnormal vessel wall reactions (AVWR), though uncommon may be associated with serious clinical events. We report on a series of patients in whom symptoms developed despite patent stents.
METHODS AND RESULTS: We report a series of 10 consecutive patients with evidence of AVWR on angiography and/or intravascular ultrasonography after implantation of sirolimus-eluting stents (age 39-90 years, 4 females) during a period of 4 years. All patients were symptomatic despite patent stents in coronary angiographies done because of persistent chest pain. Four patients subsequently developed very late stent thrombosis (VLST). These 4 patients were only on aspirin monotherapy prior to the VLST. Of the remaining 6 patients, 3 patients underwent coronary interventions (with or without stenting) while the remaining 3 patients were managed conservatively. All 6 were advised for life-long dual antiplatelet therapy.
CONCLUSION: Though uncommon, AVWR might precede VLST. In our series, all patients were symptomatic despite patent stents. Additional studies are required to identify patients at risk and to determine the best treatment modality for this challenging new entity. Until further data become available, these patients should stay on dual antiplatelet therapy after an AVWR has been identified.

PMID: 22652316 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22652316?dopt=Abstract

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Post-transplantation encapsulating peritoneal sclerosis in a pediatric patient.

Post-transplantation encapsulating peritoneal sclerosis in a pediatric patient.

Pediatr Nephrol. 2012 Apr 24;

Authors: da Silva N, Rocha S, Rocha L, Faria S, Costa T, Mota C

Abstract
BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis (PD), but only a few cases have been described in the pediatric patient population. There is no established medical treatment, and surgery has been reported with variable success. The number of reports of EPS being successfully treated with tamoxifen, based on its anti-fibrotic effects, are increasing. The role of sirolimus, an mTOR inhibitor with immunomodulatory and anti-proliferative properties, has been less well-defined. CASE-DIAGNOSIS/TREATMENT: A 17-year-old kidney transplant recipient, with a previous cumulative time on PD of 8 years and 3 months, developed severe bowel obstruction 8 months after undergoing a second kidney graft. Her immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. The patient underwent laparotomy, which revealed multiple thick leathery adhesions with an encapsulated small bowel. Enterolysis was performed, and total parenteral nutrition was commenced after surgery to provide an adequate food intake. Treatment with tamoxifen was initiated, but the patient developed significant liver toxicity 2 weeks later, and the drug was withdrawn. The immunosuppressive regimen was changed to an increased dose of prednisolone, and tacrolimus was replaced with sirolimos. At 20Â months of follow-up, the patient remains symptom-free, with a functioning kidney transplant. CONCLUSION: Although EPS is a very rare condition in the pediatric population, it should be considered when a child or adolescent with a long-term history of PD presents with nonspecific gastrointestinal symptoms or with signs of bowel obstruction. There is an urgent need for alternative immunosuppressive protocols. The use of sirolimus in this group of patients remains controversial.

PMID: 22527536 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22527536?dopt=Abstract

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Retreatment with nedaplatin in patients with recurrent gynecological cancer after the development of hypersensitivity reaction to carboplatin.

Retreatment with nedaplatin in patients with recurrent gynecological cancer after the development of hypersensitivity reaction to carboplatin.

J Obstet Gynaecol Res. 2012 Jun 13;

Authors: Arimoto T, Oda K, Nakagawa S, Kawana K, Tsukazaki T, Adachi K, Matsumoto Y, Yano T, Kozuma S, Taketani Y

Abstract
Aim:â€‚ Platinum is a milestone drug against gynecologic malignancies. The purpose of this retrospective study was to investigate the feasibility of replacing carboplatin with nedaplatin in patients who had developed a hypersensitivity reaction to carboplatin. Material and Methods:â€‚ Fifteen patients with recurrent gynecologic cancer (12 ovarian, 1 fallopian tube, 1 endometrial and 1 cervical cancer) who had experienced a hypersensitivity reaction to carboplatin and a possible clinical indication for continuing treatment with platinum were treated with nedaplatin (80â€ƒmg/m(2) )-containing regimen. Results:â€‚ The total number of nedaplatin cycles given was 137 (range 1-29). Four (27%) patients developed hypersensitivity reactions on the second, second, fourth, and ninth administration, respectively. The severities of all the hypersensitivity reactions were grade 3 or less. The other 11 patients (73%) had no nedaplatin-associated hypersensitivity reactions. The incidence of hypersensitivity reactions in the paclitaxel and nedaplatin group (three of four, 75%) was more frequent than the docetaxel and nedaplatin group (none of seven, Pâ€ƒ=â€ƒ0.024). The objective response rate in eleven patients with measurable disease was 36% (complete response at 9% and partial response at 27%), and the disease control rate was 73% (stable disease at 36%). Conclusion:â€‚ Nedaplatin-associated hypersensitivity reactions are not rare in patients who developed allergic reactions to carboplatin. Retreatment of carboplatin-allergic patients with nedaplatin cannot be recommended without careful consideration of the potential risks and benefits.

PMID: 22690725 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22690725?dopt=Abstract

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2012年7月5日星期四

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

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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Toll-like Receptor 3 Activation Affects Serotonin Transporter Activity and Expression in Human Enterocyte-like Caco-2 Cells.

Toll-like Receptor 3 Activation Affects Serotonin Transporter Activity and Expression in Human Enterocyte-like Caco-2 Cells.

Cell Physiol Biochem. 2012;30(1):187-98

Authors: Mendoza C, Matheus N, Latorre E, Castro M, Mesonero JE, Alcalde AI

Abstract
Serotonin, a neurotransmitter/autocrineagent mainly synthesized by intestinal enterochromaffin cells, regulates the whole intestinal physiology. Toll-like receptor 3 (TLR3) also contributes to the intestinal physiology by modulating intestinal innate immunity responses. Both serotonin and TLR3 are involved in intestinal inflammatory processes; however, the role of TLR3 in the regulation of intestinal 5-HT availability remains unexplored. The present study analyzes the effect of TLR3 activation on serotonin transporter (SERT) activity in Caco-2 cells. Treatment with poly(I:C), dsRNA synthetic analogue and TLR3 ligand, was assayed and SERT activity determined by 5-HT uptake and transepithelial flux. SERT expression was analyzed by qRT-PCR and western blotting. Poly(I:C) short-term treatment inhibited SERT activity in the apical and basal membrane of epithelial cells and diminished SERT protein content in the membrane. SERT total protein and mRNA levels were not affected by poly(I:C), suggesting a post-translational alteration of SERT. The poly(I:C) effect on SERT activity did not appear to be mediated by PKC, cAMP, PKR or JNK signaling pathways; however, the p38 MAPK pathway seemed to be involved. Our results demonstrate that TLR3 inhibits SERT activity, which may increase 5-HT extracellular levels and contribute to the inflammatory response; however, 5-HT treatment did not affect TLR3 expression.

PMID: 22759966 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22759966?dopt=Abstract

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

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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2012年7月4日星期三

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

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

PMID: 22753697 [PubMed - in process]

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

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

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

PMID: 22753697 [PubMed - in process]

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

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Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma.

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma.

Int J Oncol. 2012 Jun 28;

Authors: Isozaki Y, Hoshino I, Nohata N, Kinoshita T, Akutsu Y, Hanari N, Mori M, Yoneyama Y, Akanuma N, Takeshita N, Maruyama T, Seki N, Nishino N, Yoshida M, Matsubara H

Abstract
The aim of this study was to determine whether histone acetylation regulates tumor suppressive microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC) and to identify genes which are regulated by these miRNAs. We identified a miRNA that was highly upregulated in an ESCC cell line by cyclic hydroxamic acid-containing peptide 31 (CHAP31), one of the histone deacetylase inhibitors (HDACIs), using a miRNA array analysis. miR-375 was strongly upregulated by CHAP31 treatment in an ESCC cell line. The expression levels of the most upregulated miRNA, miR-375 were analyzed by quantitative real-time PCR in human ESCC specimens. The tumor suppressive function of miR-375 was revealed by restoration of miR-375 in ESCC cell lines. We performed a microarray analysis to identify target genes of miR-375. The mRNA and protein expression levels of these genes were verified in ESCC clinical specimens. LDHB and AEG-1/MTDH were detected as miRâ€‘375-targeted genes. The restoration of miR-375 suppressed the expression of LDHB and AEG-1/MTDH. The ESCC clinical specimens exhibited a high level of LDHB expression at both the mRNA and protein levels. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene. Knockdown of LDHB by RNAi showed a tumor suppressive function in the ESCC cells. The correlation between gene expression and clinicopathological features was investigated by immunohistochemistry for 94 cases of ESCC. The positive staining of LDHB correlated significantly with lymph node metastasis and tumor stage. It also had a tendency to be associated with a poor prognosis. Our results indicate that HDACIs upregulate miRNAs, at least some of which act as tumor suppressors. LDHB, which is regulated by the tumor suppressive miR-375, may therefore act as an oncogene in ESCC.

PMID: 22752059 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22752059?dopt=Abstract

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2012年7月3日星期二

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

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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Imaging P2X4 receptor lateral mobility in microglia: regulation by calcium and p38 MAPK.

Imaging P2X4 receptor lateral mobility in microglia: regulation by calcium and p38 MAPK.

J Biol Chem. 2012 Apr 27;287(18):14734-48

Authors: Toulme E, Khakh BS

Abstract
ATP-gated ionotropic P2X4 receptors are up-regulated in activated microglia and are critical for the development of neuropathic pain, a microglia-associated disorder. However, the nature of how plasma membrane P2X4 receptors are regulated in microglia is not fully understood. We used single-molecule imaging to track quantum dot-labeled P2X4 receptors to explore P2X4 receptor mobility in the processes of resting and activated microglia. We find that plasma membrane P2X4 receptor lateral mobility in resting microglial processes is largely random, consisting of mobile and slowly mobile receptors. Moreover, lateral mobility is P2X subunit- and cell-specific, increased in an ATP activation and calcium-dependent manner, and enhanced in activated microglia by the p38 MAPK pathway that selectively regulates slowly mobile receptors. Thus, our data indicate that P2X4 receptors are dynamically regulated mobile ATP sensors, sampling more of the plasma membrane in response to ATP and during the activated state of microglia that is associated with nervous system dysfunction.

PMID: 22393055 [PubMed - indexed for MEDLINE]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22393055?dopt=Abstract

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Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia.

Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia.

Blood. 2012 May 31;119(22):5201-10

Authors: Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, Carroll WL

Abstract
Whereas the improvement in outcome for children with acute lymphoblastic leukemia has been gratifying, the poor outcome of patients who relapse warrants novel treatment approaches. Previously, we identified a characteristic relapse-specific gene expression and methylation signature associated with chemoresistance using a large cohort of matched-diagnosis relapse samples. We hypothesized that "reversing" such a signature might restore chemosensitivity. In the present study, we demonstrate that the histone deacetylase inhibitor vorinostat not only reprograms the aberrant gene expression profile of relapsed blasts by epigenetic mechanisms, but is also synergistic when applied before chemotherapy in primary patient samples and leukemia cell lines. Furthermore, incorporation of the DNA methyltransferase inhibitor decitabine led to reexpression of genes shown to be preferentially methylated and silenced at relapse. Combination pretreatment with vorinostat and decitabine resulted in even greater cytotoxicity compared with each agent individually with chemotherapy. Our results indicate that acquisition of chemo-resistance at relapse may be driven in part by epigenetic mechanisms. Incorporation of these targeted epigenetic agents to the standard chemotherapy backbone is a promising approach to the treatment of relapsed pediatric acute lymphoblastic leukemia.

PMID: 22496163 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22496163?dopt=Abstract

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Secondary Epstein-Barr virus associated lymphoproliferative disorder developing in a patient with angioimmunoblastic T cell lymphoma on vorinostat.

Secondary Epstein-Barr virus associated lymphoproliferative disorder developing in a patient with angioimmunoblastic T cell lymphoma on vorinostat.

Am J Hematol. 2012 May 21;

Authors: Smeltzer JP, Viswanatha DS, Habermann TM, Patnaik MM

PMID: 22718468 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22718468?dopt=Abstract

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2012年7月2日星期一

Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.

Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.

J Pediatr Surg. 2012 Jun;47(6):1267-71

Authors: Lautz TB, Naiditch JA, Clark S, Chu F, Madonna MB

Abstract
BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat).
METHODS: In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks.
RESULTS: Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively).
CONCLUSIONS: Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin.

PMID: 22703804 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22703804?dopt=Abstract

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Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.

Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.

J Pediatr Surg. 2012 Jun;47(6):1267-71

Authors: Lautz TB, Naiditch JA, Clark S, Chu F, Madonna MB

PMID: 22703804 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22703804?dopt=Abstract

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Novel therapeutics in multiple myeloma.

Novel therapeutics in multiple myeloma.

Hematology. 2012 Apr;17 Suppl 1:S105-8

Authors: Stewart AK

Abstract
Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation.

PMID: 22507794 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22507794?dopt=Abstract

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