Journal of pharmaceutical sciences and pharmacology最新文献

{"title":"Molecular Mechanism of <i>β</i>-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers.","authors":"Sharif Morsalin, Chunshu Yang, Jinbo Fang, Sampreet Reddy, Shubhalaxmi Kayarthodi, Ed Childs, Roland Matthews, Veena N Rao, E Shyam P Reddy","doi":"10.1166/jpsp.2015.1069","DOIUrl":"10.1166/jpsp.2015.1069","url":null,"abstract":"<p><p>In the United States of America, prostate cancer is the second most common age-related cancer among men. African-American men have the highest incidence of, and mortality rate from this disease in the United States. According to the American Cancer Society, 29% of all cancer cases and 9% of all cancer deaths are a result of prostate cancer. Individuals who are at highest risk include African-American men, men over 60 years of age, and those with a family history of the disease. African-Americans also have twice the risk of developing prostate cancer as compared to Caucasians. Erythroblastosis virus E26 transformation-specific (ETS) factors play an important role in human cancers. ETS Variant 1 (ETV1), an ETS factor, is notable for its association in prostate cancers, where truncated ETV1 (dETV1) or its full length counterpart is overexpressed in approximately 10% of the prostate cancer patients. Prostate cancer tumorigenesis may be initiated by deregulation of the Wnt/<i>β</i>-catenin pathway. Mutations that stabilize <i>β</i>-catenin were shown to contribute to the loss of cell-growth control in tumorigenesis. We hypothesized that ETV1's interaction with components of the Wnt/<i>β</i>-catenin pathway may alter <i>β</i>-catenin's interaction with downstream tumor-suppressor genes, which are critical in regulating apoptosis and cell-growth properties of prostate cells. Our results demonstrate for the first time that ETV1 alters <i>β</i>-catenin activity by activating kinases that regulate Wnt/<i>β</i>-catenin activity through post-translational modification in prostate cancer cells. We further demonstrate that therapeutic agents such as PD98059, that reverse effect of ETV1 on Wnt/<i>β</i>-catenin signaling pathway, can be used to target ETV1-positive prostate cancer cells. These therapeutic agents could have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority patients. Understanding the role of ETV1 in Wnt/<i>β</i>-catenin pathway will also allow us to develop better diagnostic tools, which can be used as a biomarker for ETV1-positive prostate cancers.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"2 3","pages":"208-216"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423671/pdf/nihms823088.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34990100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells.","authors":"Jinbo Fang,&nbsp;Huali Xu,&nbsp;Chunshu Yang,&nbsp;Sharif Morsalin,&nbsp;Shubhalaxmi Kayarthodi,&nbsp;Kunchala Rungsrisuriyachai,&nbsp;Ujwala Gunnal,&nbsp;Brittany Mckenzie,&nbsp;Veena N Rao,&nbsp;E Shyam P Reddy","doi":"10.1166/jpsp.2014.1022","DOIUrl":"https://doi.org/10.1166/jpsp.2014.1022","url":null,"abstract":"<p><p>TGF-<i>β</i>/Smads signaling plays a significant role in the regulation of growth of normal and prostate cancer cells. Smad proteins function as important mediators of intracellular signal transduction of transforming growth factor-<i>β</i> (TGF-<i>β</i>). TGF-<i>β</i> signaling pathway is known to regulate cell proliferation, differentiation, apoptosis and play a major role in some human diseases and cancers. Following their phosphorylation by TGF-<i>β</i> receptor-I, Receptor-regulated Smads (including Smad2 and Smad3 proteins) form a heteromeric complex with co-Smad (Smad4) and then translocate into the nucleus where they bind and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in majority of prostate cancers. Over-expression of full length or truncated ERG proteins have been shown to associate with a higher rate of recurrent and unfavorable prognosis of prostate cancer. In order to understand how ERG oncoprotein regulates TGF-<i>β</i>/Smads signaling pathway, we have studied the effect of ERG on TGF-<i>β</i>/Smad3 signaling pathway. In this study, we demonstrate that ERG oncoprotein physically interacts with Smad3 protein and stabilizes phospho-Smad3 protein and thereby enhance TGF-<i>β</i>/Smad3 signaling pathway in prostate cells. Thus, ERG oncoprotein plays an important role in prostate tumorigenesis by using a novel mechanism to activate TGF-<i>β</i>/Smad3 signaling pathway.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 3","pages":"175-181"},"PeriodicalIF":0.0,"publicationDate":"2014-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1166/jpsp.2014.1022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33108124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Epidermal Growth Factor Stimulated ERK Phosphorylation and Cell Motility by Inositol Trisphosphate Kinase.","authors":"M C Sekar,&nbsp;K Shahiwala,&nbsp;L Leloup,&nbsp;A Wells","doi":"10.1166/jpsp.2014.1010","DOIUrl":"https://doi.org/10.1166/jpsp.2014.1010","url":null,"abstract":"<p><p>Epidermal growth factor [EGF] mediated stimulation of its receptor in endothelial cell [EC] is accompanied by phosphorylation of the EGF-receptor [EGFR] and activation of phospholipase C-<i>γ</i>, resulting in the breakdown of phosphatidylinositol(4,5)-bisphosphate and generating inositol (1,4,5)-trisphosphate [IP₃] and diacylglycerol. IP₃ thus formed can be further converted to inositol (1,3,4,5)-tetrakisphosphate [IP₄] by an enzyme called IP₃-kinase [IP₃K]. In this study we have investigated the effect of modulation of intracellular IP₃K activity by the use of an inhibitor, 2-trifluoromethyl [6-(4-nitrobenzyl)-purine] [IP₃KI] and siRNA against IP₃KB on EGF-induced ERK-phosphorylation and cell motility. EGF stimulated ERK-phosphorylation that has been implicated in EGF-stimulated cell migration was inhibited by both IP₃KI and siRNA against IP₃KB. Inhibition of ERK-phosphorylation was accompanied by decreased cell migration in the presence of IP₃KI.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 2","pages":"160-164"},"PeriodicalIF":0.0,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1166/jpsp.2014.1010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33871087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-Epileptic Drug Targets Ewing Sarcoma.","authors":"Shubhalaxmi Kayarthodi,&nbsp;Yasuo Fujimura,&nbsp;Jinbo Fang,&nbsp;Sharif Morsalin,&nbsp;Veena N Rao,&nbsp;E Shyam P Reddy","doi":"10.1166/jpsp.2014.1013","DOIUrl":"https://doi.org/10.1166/jpsp.2014.1013","url":null,"abstract":"<p><p>Ewing Sarcoma (ES) is a rare form of bone cancer that most commonly affects children and adolescents. Chromosomal translocations are fundamental to the development of Ewing Sarcoma, linked to the changes in gene expression affecting transcription factors. Histone acetyl transferases (HATs) and histone deacetylases (HDACs) regulate transcription by modifying acetylation of both histones and transcription factors. Despite the use of multimodal therapeutic approaches current therapies are associated with significant short and long-term side effects. Hence, new therapeutic approaches are needed. In this study, we show that ERG/EWS-ERG, inhibits transcriptional activation properties of RXR<i>α</i>. These results suggest that ERG/EWS-ERG/EWS-Fli-1 may target transcriptional co-activators and transcriptional repressors and thereby regulate RXR<i>α</i> transcriptional activity. To understand the molecular mechanism of action, how the fusion protein targets nuclear receptor function, and to provide a clue for the cancer health disparity seen in Ewing Sarcoma, we hypothesized that the aberrant fusion protein, EWS-ERG/EWS-Fli-1 regulates HDACs-mediated repressor complex and inhibits the binding of transcriptional activator complex causing transcriptional repression of RXR<i>α</i> activity. Since it is known that HDACs regulate nuclear receptors, we proposed that HDAC inhibitor, valproic acid (VPA), an anti-epileptic drug, may reverse the inhibitory properties of EWS-ERG/EWS-Fli-1 oncoprotein on RXR<i>α</i> transcriptional activity and might therefore be used as therapeutic agent in ES. We demonstrate that VPA reverses the inhibitory effect of EWSERG/EWS-Fli-1 on RXR<i>α</i> transcriptional activity and also inhibits the cell growth. Furthermore, VPA induces apoptosis and restored the expression of RXR<i>α</i> target genes RAR<i>β</i>, CRABPII and p21 activity and repressed the expression of aberrant fusion proteins, EWS-ERG and EWS-Fli-1 in Ewing Sarcoma cells. Thus, therapeutic regulation of transcriptional repressor properties of EWS-ERG/EWS-Fli-1 with an anti-epileptic drug with a promising new potential might have a profound impact on prevention, management and treatment of Ewing Sarcoma. Therapeutic use of VPA in minority patients may help reduce the health disparity.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 2","pages":"87-100"},"PeriodicalIF":0.0,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1166/jpsp.2014.1013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33039893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A One-Step Synthesis of β-Bromocodide from Codeine.","authors":"C. Cunningham, J. Deschamps, A. Coop","doi":"10.1166/JPSP.2014.1005","DOIUrl":"https://doi.org/10.1166/JPSP.2014.1005","url":null,"abstract":"Opioid analgesics are the treatment of choice for chronic, severe pain. During the course of developing new derivatives of morphine and codeine, we observed an unanticipated SN2' substitution reaction product during an attempted 3-O-demethylation of codeine using BBr3. NMR spectroscopy and X-ray crystallographic data indicate that a significant product is β-bromocodide, a useful intermediate for the production of C-6-demethoxythebaine derivatives. Herein we report the first, single-step synthesis of β-bromocodide.","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 1 1","pages":"54-56"},"PeriodicalIF":0.0,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1166/JPSP.2014.1005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64648126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanism of Activation of Transforming Growth Factor Beta/Smads Signaling Pathway in Ets Related Gene-Positive Prostate Cancers.","authors":"Jinbo Fang,&nbsp;Huali Xu,&nbsp;Chunshu Yang,&nbsp;Shubha Kayarthodi,&nbsp;Roland Matthews,&nbsp;Veena N Rao,&nbsp;E Shyam P Reddy","doi":"10.1166/jpsp.2014.1008","DOIUrl":"https://doi.org/10.1166/jpsp.2014.1008","url":null,"abstract":"<p><p>Transforming growth factor beta (TGF-β) signaling pathway is involved in diverse cellular processes, including cell proliferation, differentiation, adhesion, apoptosis, and some human diseases including cancer. Smad proteins function as mediators of intracellular signal transduction of TGF-β. Following their phosphorylation by TGF-β receptor I, Smad2 and Smad3 form a heteromeric complex with Smad4 and then are translocated into the nucleus where they bind to other co-factors and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in the majority of prostate cancers. Over-expression of full length or truncated ERG proteins is associated with a higher rate of recurrence and unfavorable prognosis. In this review, we focus on recent understanding of regulation of TGF-β/Smads signaling pathway by ERG proteins in prostate cancer.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 1","pages":"82-85"},"PeriodicalIF":0.0,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1166/jpsp.2014.1008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33052347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A One-Step Synthesis of <i>β</i>-Bromocodide from Codeine.","authors":"Christopher W Cunningham,&nbsp;Jeffrey R Deschamps,&nbsp;Andrew Coop","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Opioid analgesics are the treatment of choice for chronic, severe pain. During the course of developing new derivatives of morphine and codeine, we observed an unanticipated S_N2' substitution reaction product during an attempted 3-O-demethylation of codeine using BBr₃. NMR spectroscopy and X-ray crystallographic data indicate that a significant product is <i>β</i>-bromocodide, a useful intermediate for the production of C-6-demethoxythebaine derivatives. Herein we report the first, single-step synthesis of <i>β</i>-bromocodide.</p>","PeriodicalId":90906,"journal":{"name":"Journal of pharmaceutical sciences and pharmacology","volume":"1 1","pages":"54-56"},"PeriodicalIF":0.0,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474124/pdf/nihms-1741550.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39466704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}