The Experts below are selected from a list of 654 Experts worldwide ranked by ideXlab platform
Zoltan Szallasi - One of the best experts on this subject based on the ideXlab platform.
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Nonpromoting 12-Deoxyphorbol 13-Esters Inhibit Phorbol 12-Myristate 13-Acetate Induced Tumor Promotion in CD-1 Mouse Skin
Cancer research, 1993Co-Authors: Zoltan Szallasi, Ljubica Krsmanovic, Peter M BlumbergAbstract:Prostratin and 12-deoxyphorbol 13-phenylacetate (dPP) form a new class of protein kinase C activators of unique biological activity. Although they bind to and activate protein kinase C, in mouse skin they either fail to induce typical phorbol ester (PMA) effects (e.g., hyperplasia) or induce only partial response (e.g., inflammation). Furthermore, pretreatment with these agents inhibits a range of PMA induced effects (acute and chronic hyperplasia, inflammation, etc.) These observations suggested that Prostratin and dPP would function as inhibitors of phorbol ester tumor promotion. Here we verify that prediction. We report that both compounds reduced both the average number of papillomas and the tumor incidence in a tumor promotion schedule in CD-1 mouse skin, in which each PMA application was preceded by 12-deoxyphorbol 13-monoester pretreatment. The highest dose of Prostratin used (2.56 mumol or 1 mg/pretreatment) caused a 96% (23-fold) reduction in the average number of papillomas with a decrease of tumor incidence from 97 to 40%. The highest dose of dPP used (21.4 nmol or 10 micrograms/pretreatment) induced an 86% (7-fold) reduction in the average number of papillomas with a 53% reduction of tumor incidence from 100 to 47%. The inhibitory effect was dose dependent. The dose causing 50% inhibition was 11 nmol/pretreatment for Prostratin and 0.8 nmol/pretreatment for dPP. Maximal inhibition of tumor promotion was accompanied by a block of epidermal hyperplasia; however, significant inhibition of tumor induction was observed at doses without any apparent effect on the PMA induced hyperplasia.
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Non-promoting 12-deoxyphorbol 13-esters as potent inhibitors of phorbol 12-myristate 13-acetate-induced acute and chronic biological responses in CD-1 mouse skin
Carcinogenesis, 1992Co-Authors: Zoltan Szallasi, Kristopher W. KrauszAbstract:In previous experiments, pretreatment of CD-1 mouse skin with Prostratin (12-deoxyphorbol 13-acetate) inhibited hyperplasia, induction of ornithine decarboxylase and edema in response to acute treatment with phorbol 12-myristate 13-acetate (PMA). We report here that Prostratin inhibits biological responses induced by multiple (chronic) PMA treatment. A typical chronic treatment schedule consisted of five applications of 3.2 nmol (2 micrograms) PMA at 48 h intervals. Most effective inhibition could be achieved when the first PMA treatment was preceded 48 h before by a lower dose of Prostratin (256 nmol = 100 micrograms) and each PMA treatment was preceded 15 min before by a higher dose (2.56 mumol = 1 mg) of Prostratin. Under this schedule hyperplasia was completely blocked, as was keratin K6 expression (a marker of hyperproliferative epidermis), whereas myeloperoxidase activity (a marker of neutrophil granulocyte infiltration) was reduced to 36%. 12-Deoxyphorbol 13-phenylacetate (dPP), a non-promoting 12-deoxyphorbol derivative that binds to protein kinase C with two orders of magnitude higher potency than does Prostratin, showed the same pattern of inhibition as did Prostratin for a single PMA treatment but with a corresponding two orders of magnitude higher potency. In the case of chronic PMA treatment, however, dPP failed to inhibit hyperplasia fully, though it reduced keratin K6 expression and inflammation. Dissociation of K6 expression from hyperplasia was unexpected, since expression of these two responses was thought to be closely coupled. We conclude that 12-deoxyphorbol 13-monoesters are functional antagonists for a class of protein kinase C-mediated responses closely correlated to tumor promotion.
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Prostratin, a nonpromoting phorbol ester, inhibits induction by phorbol 12-myristate 13-acetate of ornithine decarboxylase, edema, and hyperplasia in CD-1 mouse skin.
Cancer research, 1991Co-Authors: Zoltan SzallasiAbstract:Abstract Pretreatment of CD-1 mouse skin with Prostratin (12-deoxyphorbol 13-acetate) inhibited biological response to phorbol 12-myristate 13-acetate. The three responses examined were hyperplasia, induction of ornithine decarboxylase, and edema; the characteristics of inhibition depended on the specific response. Hyperplasia is the best short-term correlate of tumor promotion. Two or more pretreatments with 2.56 µmol (1 mg) Prostratin, administered at intervals of 1–4 days, almost completely blocked the hyperplasia induced by phorbol 12-myristate 13-acetate applied 15 min to 6 h after the last pretreatment. Inducibility of hyperplasia was partially restored at 2 days and recovered by 4 days. Prostratin was more potent for inhibition of ornithine decarboxylase induction (50% inhibitory dose = 25.6 nmol) than it was for hyperplasia: the inhibition was largely attained by the first application, and the recovery from inhibition was slower (8 days). Edema was partially inhibited by Prostratin (dose giving 50% of maximal inhibition = 512 nmol). We have previously demonstrated that Prostratin is a protein kinase C activator. Our present results show that Prostratin is a functional antagonist for a class of protein kinase C mediated responses. The findings emphasize the diversity of biological outcome for protein kinase C activators, presumably driven by the extensive heterogeneity in the protein kinase C pathway.
Peter M Blumberg - One of the best experts on this subject based on the ideXlab platform.
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activation of latent hiv 1 expression by the potent anti tumor promoter 12 deoxyphorbol 13 phenylacetate
Antiviral Research, 2003Co-Authors: Sven Bocklandt, Peter M Blumberg, Dean H HamerAbstract:Agents that induce HIV-1 out of latency would be useful adjuvants for currently available anti-retroviral therapy. We report that nanomolar concentrations of 12-deoxyphorbol 13-phenylacetate (DPP), an anti-tumor-promoting phorbol ester originally isolated from a West African plant, induce the expression of HIV-1 in latently infected T cells and render them sensitive to killing by an immunotoxin targeted to the viral envelope glycoprotein. DPP also regulates an extensive series of genes under the control of protein kinase C, including several involved in T cell activation and cytoskeleton reorganization, and represses expression of the HIV-1 receptor CD4 and coreceptor CXCR4. DPP is 20-40-fold more potent than the related phorbol ester Prostratin, probably due to its more lipophilic side chain structure. The combination of high potency and anti-tumor promoting activity make DPP an attractive candidate for the adjunctive therapy of persistent HIV-1 infection.
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Nonpromoting 12-Deoxyphorbol 13-Esters Inhibit Phorbol 12-Myristate 13-Acetate Induced Tumor Promotion in CD-1 Mouse Skin
Cancer research, 1993Co-Authors: Zoltan Szallasi, Ljubica Krsmanovic, Peter M BlumbergAbstract:Prostratin and 12-deoxyphorbol 13-phenylacetate (dPP) form a new class of protein kinase C activators of unique biological activity. Although they bind to and activate protein kinase C, in mouse skin they either fail to induce typical phorbol ester (PMA) effects (e.g., hyperplasia) or induce only partial response (e.g., inflammation). Furthermore, pretreatment with these agents inhibits a range of PMA induced effects (acute and chronic hyperplasia, inflammation, etc.) These observations suggested that Prostratin and dPP would function as inhibitors of phorbol ester tumor promotion. Here we verify that prediction. We report that both compounds reduced both the average number of papillomas and the tumor incidence in a tumor promotion schedule in CD-1 mouse skin, in which each PMA application was preceded by 12-deoxyphorbol 13-monoester pretreatment. The highest dose of Prostratin used (2.56 mumol or 1 mg/pretreatment) caused a 96% (23-fold) reduction in the average number of papillomas with a decrease of tumor incidence from 97 to 40%. The highest dose of dPP used (21.4 nmol or 10 micrograms/pretreatment) induced an 86% (7-fold) reduction in the average number of papillomas with a 53% reduction of tumor incidence from 100 to 47%. The inhibitory effect was dose dependent. The dose causing 50% inhibition was 11 nmol/pretreatment for Prostratin and 0.8 nmol/pretreatment for dPP. Maximal inhibition of tumor promotion was accompanied by a block of epidermal hyperplasia; however, significant inhibition of tumor induction was observed at doses without any apparent effect on the PMA induced hyperplasia.
Ian Tietjen - One of the best experts on this subject based on the ideXlab platform.
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Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products.
Viruses, 2018Co-Authors: Khumoekae Richard, David E. Williams, E. Dilip De Silva, Mark A. Brockman, Zabrina L. Brumme, Raymond J. Andersen, Ian TietjenAbstract:Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as Prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator Prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not Prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs.
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sesterterpenoids isolated from the sponge phorbas sp activate latent hiv 1 provirus expression
Journal of Organic Chemistry, 2016Co-Authors: Meng Wang, David E. Williams, Mark A. Brockman, Ian Tietjen, Julie Daoust, Min Chen, Raymond J. AndersenAbstract:Eight new sesterterpenoids, alotaketals D (8) and E (9), ansellones D (10), E (11), F (12), and G (13), and anvilones A (14) and B (15), have been isolated from extracts of the marine sponge Phorbas sp. collected in Howe Sound British Columbia, and their structures have been elucidated by analysis of NMR and MS data. Ansellone F (12) contains a rare 1,2–3,4-bis-epoxydecalin substructure. Anvilones A (14) and B (15) have an unprecedented tetracylic anvilane terpenoid carbon skeleton. Using a cell culture model of latent HIV-1 infection, ansellone A (3), alotaketal D (8), and anvilone A (14) were found to induce HIV proviral gene expression similar to the control compound Prostratin (1), while the known sesterterpenoid alotaketal C (2), isolated from the same extract, was more potent and gave a stronger response than Prostratin (1). Like Prostratin (1), all of the Phorbas sesterterpenoids with latency reversal agent properties appear to activate protein kinase C signaling.
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Sesterterpenoids Isolated from the Sponge Phorbas sp. Activate Latent HIV‑1 Provirus Expression
2016Co-Authors: Meng Wang, Mark A. Brockman, Ian Tietjen, Julie Daoust, Min Chen, David E. Williams, Raymond J. AndersenAbstract:Eight new sesterterpenoids, alotaketals D (8) and E (9), ansellones D (10), E (11), F (12), and G (13), and anvilones A (14) and B (15), have been isolated from extracts of the marine sponge Phorbas sp. collected in Howe Sound British Columbia, and their structures have been elucidated by analysis of NMR and MS data. Ansellone F (12) contains a rare 1,2–3,4-bis-epoxydecalin substructure. Anvilones A (14) and B (15) have an unprecedented tetracylic anvilane terpenoid carbon skeleton. Using a cell culture model of latent HIV-1 infection, ansellone A (3), alotaketal D (8), and anvilone A (14) were found to induce HIV proviral gene expression similar to the control compound Prostratin (1), while the known sesterterpenoid alotaketal C (2), isolated from the same extract, was more potent and gave a stronger response than Prostratin (1). Like Prostratin (1), all of the Phorbas sesterterpenoids with latency reversal agent properties appear to activate protein kinase C signaling
Raymond J. Andersen - One of the best experts on this subject based on the ideXlab platform.
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Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products.
Viruses, 2018Co-Authors: Khumoekae Richard, David E. Williams, E. Dilip De Silva, Mark A. Brockman, Zabrina L. Brumme, Raymond J. Andersen, Ian TietjenAbstract:Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as Prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator Prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not Prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs.
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sesterterpenoids isolated from the sponge phorbas sp activate latent hiv 1 provirus expression
Journal of Organic Chemistry, 2016Co-Authors: Meng Wang, David E. Williams, Mark A. Brockman, Ian Tietjen, Julie Daoust, Min Chen, Raymond J. AndersenAbstract:Eight new sesterterpenoids, alotaketals D (8) and E (9), ansellones D (10), E (11), F (12), and G (13), and anvilones A (14) and B (15), have been isolated from extracts of the marine sponge Phorbas sp. collected in Howe Sound British Columbia, and their structures have been elucidated by analysis of NMR and MS data. Ansellone F (12) contains a rare 1,2–3,4-bis-epoxydecalin substructure. Anvilones A (14) and B (15) have an unprecedented tetracylic anvilane terpenoid carbon skeleton. Using a cell culture model of latent HIV-1 infection, ansellone A (3), alotaketal D (8), and anvilone A (14) were found to induce HIV proviral gene expression similar to the control compound Prostratin (1), while the known sesterterpenoid alotaketal C (2), isolated from the same extract, was more potent and gave a stronger response than Prostratin (1). Like Prostratin (1), all of the Phorbas sesterterpenoids with latency reversal agent properties appear to activate protein kinase C signaling.
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Sesterterpenoids Isolated from the Sponge Phorbas sp. Activate Latent HIV‑1 Provirus Expression
2016Co-Authors: Meng Wang, Mark A. Brockman, Ian Tietjen, Julie Daoust, Min Chen, David E. Williams, Raymond J. AndersenAbstract:Eight new sesterterpenoids, alotaketals D (8) and E (9), ansellones D (10), E (11), F (12), and G (13), and anvilones A (14) and B (15), have been isolated from extracts of the marine sponge Phorbas sp. collected in Howe Sound British Columbia, and their structures have been elucidated by analysis of NMR and MS data. Ansellone F (12) contains a rare 1,2–3,4-bis-epoxydecalin substructure. Anvilones A (14) and B (15) have an unprecedented tetracylic anvilane terpenoid carbon skeleton. Using a cell culture model of latent HIV-1 infection, ansellone A (3), alotaketal D (8), and anvilone A (14) were found to induce HIV proviral gene expression similar to the control compound Prostratin (1), while the known sesterterpenoid alotaketal C (2), isolated from the same extract, was more potent and gave a stronger response than Prostratin (1). Like Prostratin (1), all of the Phorbas sesterterpenoids with latency reversal agent properties appear to activate protein kinase C signaling
Kristopher W. Krausz - One of the best experts on this subject based on the ideXlab platform.
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Non-promoting 12-deoxyphorbol 13-esters as potent inhibitors of phorbol 12-myristate 13-acetate-induced acute and chronic biological responses in CD-1 mouse skin
Carcinogenesis, 1992Co-Authors: Zoltan Szallasi, Kristopher W. KrauszAbstract:In previous experiments, pretreatment of CD-1 mouse skin with Prostratin (12-deoxyphorbol 13-acetate) inhibited hyperplasia, induction of ornithine decarboxylase and edema in response to acute treatment with phorbol 12-myristate 13-acetate (PMA). We report here that Prostratin inhibits biological responses induced by multiple (chronic) PMA treatment. A typical chronic treatment schedule consisted of five applications of 3.2 nmol (2 micrograms) PMA at 48 h intervals. Most effective inhibition could be achieved when the first PMA treatment was preceded 48 h before by a lower dose of Prostratin (256 nmol = 100 micrograms) and each PMA treatment was preceded 15 min before by a higher dose (2.56 mumol = 1 mg) of Prostratin. Under this schedule hyperplasia was completely blocked, as was keratin K6 expression (a marker of hyperproliferative epidermis), whereas myeloperoxidase activity (a marker of neutrophil granulocyte infiltration) was reduced to 36%. 12-Deoxyphorbol 13-phenylacetate (dPP), a non-promoting 12-deoxyphorbol derivative that binds to protein kinase C with two orders of magnitude higher potency than does Prostratin, showed the same pattern of inhibition as did Prostratin for a single PMA treatment but with a corresponding two orders of magnitude higher potency. In the case of chronic PMA treatment, however, dPP failed to inhibit hyperplasia fully, though it reduced keratin K6 expression and inflammation. Dissociation of K6 expression from hyperplasia was unexpected, since expression of these two responses was thought to be closely coupled. We conclude that 12-deoxyphorbol 13-monoesters are functional antagonists for a class of protein kinase C-mediated responses closely correlated to tumor promotion.
