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Bryostatin 1

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George R. Pettit – 1st expert on this subject based on the ideXlab platform

  • Neristatin 1 provides critical insight into Bryostatin 1 structure-function relationships.
    Journal of Natural Products, 2015
    Co-Authors: Noemi Kedei, George R. Pettit, Matthew B. Kraft, Gary E. Keck, Cheery L Herald, Noeleen Melody, Peter M. Blumberg

    Abstract:

    Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, Bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the Bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the Bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of Bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is Bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the Bryostatin 1 structure is largely sufficient for Bryostatin 1-like activity, provided the molecule also possesses …

  • Synergistic action of calcium ionophore A23187 and protein kinase C activator Bryostatin 1 on human B cell activation and proliferation.
    European Journal of Immunology, 2005
    Co-Authors: Hans G. Drexler, George R. Pettit, Suzanne M. Gignac, A. Victor Hoffbrand

    Abstract:

    In this study we have examined the immunostimulatory effects of the macrocyclic lactone Bryostatin 1 on various aspects of B cell activation and proliferation using human tonsillar B cells. Bryostatin 1 is an activator of protein kinase C (PKC) and its properties were compared to those of the classical PKC activator phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Time-course kinetics and dose-response curves of RNA and DNA synthesis induced by Bryostatin 1 or PMA were comparable, albeit the phorbol ester was significantly more potent. The responses triggered by both Bryostatin 1 and PMA could be blocked by the PKC inhibitor H7. Bryostatin 1 and PMA mediated similar effects with regard to the activation parameters, increase in cell size, expression of activation-associated antigens and hyperexpression of major histocompatibility complex class II antigens. Addition of the calcium ionophore A23187 to Bryostatin 1-treated cultures resulted in synergistically enhanced activation and proliferation responses, and this potentiation by A23187 could be inhibited by cyclosporin A. Bryostatin 1 antagonized the effects of PMA-triggered stimulation in a time- and dose-dependent manner. The basis for this modulation of PMA-induced effects and the reason for the difference in the abilities of the two agents to stimulate B cells is unclear; possibly, Bryostatin 1 and PMA activate different isoforms of PKC and elicit different signals on intracellular biochemical pathways.

    Bryostatin 1 lacks the tumor-promoting activity of PMA and is a potent anti-neoplastic substance. These features together with its immunomodulatory properties qualify Bryostatin 1 as a candidate for in vivo use as a biological response modifier.

  • the transient increase of tight junction permeability induced by Bryostatin 1 correlates with rapid downregulation of protein kinase c α
    Experimental Cell Research, 2000
    Co-Authors: Hilary Clarke, George R. Pettit, Nicole Ginanni, K V Laughlin, Jeffrey B Smith, James M Mullin

    Abstract:

    Abstract The role of PKC-α in altered epithelial barrier permeability following the activation of PKC by TPA (12-O-tetradecanoyl phorbol 13-acetate) and Bryostatin 1 in LLC-PK1 cells was investigated in this study. Like TPA, Bryostatin 1 binds to and activates PKC but unlike TPA, it is not a tumor promoter. TPA at 10−7 M induced a sustained 95% decrease in transepithelial electrical resistance (Rt) across LLC-PK1 epithelial cell sheets, while 10−7 M Bryostatin 1 caused only a 30% decrease in Rt, which spontaneously reversed after 5 h. Simultaneous exposure of cell sheets to 10−7 M TPA and 10−7 M Bryostatin 1 blunted the increase in epithelial permeability observed with 10−7 M TPA alone. Co-incubation of cell sheets with Bryostatin 1 and MG-132, a proteasomal inhibitor, caused a further decrease in Rt at the 6-h time point and inhibited the recovery in Rt seen with Bryostatin 1 alone at this time point. TPA caused a rapid translocation of PKC-α from the cytosol to the membrane of the cell where it remained elevated. Bryostatin 1 treatment resulted in a slower translocation of PKC-α from the cytosol to the membrane and a much more rapid downregulation of PKC-α, with disappearance from this compartment after only 6 h. The classical PKC inhibitor Go6976 prevented the decrease in Rt seen with TPA. Treatment of cells with TPA and Bryostatin 1 resulted in a PKC-α translocation and downregulation profile which more closely resembled that seen with Bryostatin 1 alone. Co-incubation of cells with MG-132 and Bryostatin 1 caused a slower downregulation of PKC-α from the membrane fraction. Bryostatin 1 treatment of cells expressing a dominant/negative form of PKC-α resulted in a slower and less extensive decrease in Rt compared to the corresponding control cells. For both TPA and Bryostatin 1, the level of PKC-α in the membrane-associated fraction of the treated cells correlated closely with increased transepithelial permeability. Due to its transient effect on tight junction permeability, Bryostatin 1 offers a novel pharmacological tool to investigate junctional physiology.

Peter M. Blumberg – 2nd expert on this subject based on the ideXlab platform

  • Munc13 Is a Molecular Target of Bryostatin 1.
    Biochemistry, 2019
    Co-Authors: Francisco A. Blanco, Noemi Kedei, Agnes Czikora, Gary A. Mitchell, Satyabrata Pany, Anamitra Ghosh, Peter M. Blumberg

    Abstract:

    Bryostatin 1 is a natural macrolide shown to improve neuronal connections and enhance memory in mice. Its mechanism of action is largely attributed to the modulation of novel and conventional protein kinase Cs (PKCs) by binding to their regulatory C1 domains. Munc13-1 is a C1 domain-containing protein that shares common endogenous and exogenous activators with novel and conventional PKC subtypes. Given the essential role of Munc13-1 in the priming of synaptic vesicles and neuronal transmission overall, we explored the potential interaction between Bryostatin 1 and Munc13-1. Our results indicate that in vitro Bryostatin 1 binds to both the isolated C1 domain of Munc13-1 (Ki = 8.07 ± 0.90 nM) and the full-length Munc13-1 protein (Ki = 0.45 ± 0.04 nM). Furthermore, confocal microscopy and immunoblot analysis demonstrated that in intact HT22 cells Bryostatin 1 mimics the actions of phorbol esters, a previously established class of Munc13-1 activators, and induces plasma membrane translocation of Munc13-1, a h…

  • munc13 is a molecular target of Bryostatin 1
    Biochemistry, 2019
    Co-Authors: Francisco A. Blanco, Noemi Kedei, Agnes Czikora, Gary A. Mitchell, Satyabrata Pany, Anamitra Ghosh, Peter M. Blumberg

    Abstract:

    : Bryostatin 1 is a natural macrolide shown to improve neuronal connections and enhance memory in mice. Its mechanism of action is largely attributed to the modulation of novel and conventional protein kinase Cs (PKCs) by binding to their regulatory C1 domains. Munc13-1 is a C1 domain-containing protein that shares common endogenous and exogenous activators with novel and conventional PKC subtypes. Given the essential role of Munc13-1 in the priming of synaptic vesicles and neuronal transmission overall, we explored the potential interaction between Bryostatin 1 and Munc13-1. Our results indicate that in vitro Bryostatin 1 binds to both the isolated C1 domain of Munc13-1 ( Ki = 8.07 ± 0.90 nM) and the full-length Munc13-1 protein ( Ki = 0.45 ± 0.04 nM). Furthermore, confocal microscopy and immunoblot analysis demonstrated that in intact HT22 cells Bryostatin 1 mimics the actions of phorbol esters, a previously established class of Munc13-1 activators, and induces plasma membrane translocation of Munc13-1, a hallmark of its activation. Consistently, Bryostatin 1 had no effect on the Munc13-1H567K construct that is insensitive to phorbol esters. Effects of Bryostatin 1 on the other Munc13 family members, ubMunc13-2 and bMunc13-2, resembled those of Munc13-1 for translocation. Lastly, we observed an increased level of expression of Munc13-1 following a 24 h incubation with Bryostatin 1 in both HT22 and primary mouse hippocampal cells. This study characterizes Munc13-1 as a molecular target of Bryostatin 1. Considering the crucial role of Munc13-1 in neuronal function, these findings provide strong support for the potential role of Munc13s in the actions of Bryostatin 1.

  • Neristatin 1 provides critical insight into Bryostatin 1 structure-function relationships.
    Journal of Natural Products, 2015
    Co-Authors: Noemi Kedei, George R. Pettit, Matthew B. Kraft, Gary E. Keck, Cheery L Herald, Noeleen Melody, Peter M. Blumberg

    Abstract:

    Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, Bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the Bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the Bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of Bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is Bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the Bryostatin 1 structure is largely sufficient for Bryostatin 1-like activity, provided the molecule also possesses …

Andrew S Kraft – 3rd expert on this subject based on the ideXlab platform

  • Treatment of patients with metastatic melanoma with Bryostatin1–a phase II study.
    Melanoma Research, 1999
    Co-Authors: Rene Gonzalez, Scot Ebbinghaus, Thomas K. Henthorn, D. Miller, Andrew S Kraft

    Abstract:

    : Bryostatin1 is a protein kinase C regulator which has shown antitumour activity against B16 melanoma in animal models. Safety trials revealed this agent to be minimally toxic, thus a phase II trial of Bryostatin1 was conducted to determine its efficacy In patients with melanoma. Eighteen patients with metastatic melanoma, seven of whom had been previously treated, were enrolled in the study. Patients received Bryostatin1 25 microg/m2 intravenously weekly over 1 h for 3 out of 4 weeks. No objective responses were observed. One patient who had not previously received chemotherapy had stable disease for 4 months, and two patients (one previously treated) had a marked decrease in the skin component of their disease. The major toxicity was myalgia (one patient with grade III, two patients with grade II and five patients with grade I), with no grade IV toxicities reported. To Indirectly evaluate the stimulation of protein kinase C, a sensitive assay that measures the upregulation of the activated form of CD62 (glycoprotein IIb/IIIa) on platelets was performed. There was a statistically significant upregulation of this antigen 1 h after Bryostatin1 therapy. A bioassay based on the ability of Bryostatin1 to bind protein kinase C was used to measure Bryostatin1 levels in serum. This assay showed that Bryostatin1 has a volume of distribution of 2.1 l/m2, an elimination clearance of 32.9 ml/min per m2 and a half-life of 43.9 min. In conclusion, this phase II trial demonstrates that, although it is relatively non-toxic, Bryostatin1 therapy had minimal activity in metastatic melanoma.

  • a phase i trial of Bryostatin 1 in children with refractory solid tumors a pediatric oncology group study
    Clinical Cancer Research, 1999
    Co-Authors: Steven D Weitman, Andrew S Kraft, Roger L. Berkow, Annemarie R Langevin, Paul J Thomas, Craig A Hurwitz, Ronald L Dubowy, Debra L Smith, Mark L Bernstein

    Abstract:

    Bryostatin1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of Bryostatin1 was performed in children with solid tumors to: ( a ) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); ( b ) establish the pharmacokinetic profile in children; and ( c ) document any evidence of antitumor activity. A 1-h infusion of Bryostatin1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2–21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 μg/m 2 /dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 μg/m 2 /dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24–72 h after the second dose of Bryostatin1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The Bryostatin1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of Bryostatin1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 μg/m 2 /dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.

  • preclinical pharmacology of the natural product anticancer agent Bryostatin 1 an activator of protein kinase c
    Cancer Research, 1996
    Co-Authors: George R. Pettit, Xueshu Zhang, Ruiwen Zhang, Hui Zhao, Kimberly A Gush, Russell G Kerr, Andrew S Kraft

    Abstract:

    Abstract Bryostatin 1, a natural product anticancer agent isolated from a marine bryozoan, has been shown in tissue culture to activate protein kinase C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To understand how Bryostatin 1 might be used best as an anticancer agent, a study of the pharmacokinetics, tissue distribution, metabolism, and elimination of Bryostatin 1 in mice was undertaken, using [C26- 3 H]-labeled Bryostatin 1. Following i.v. administration, the plasma disappearance curve for Bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the plasma disappearance curve for Bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h after i.v administration, urinary excretion represented the major pathway of elimination, with 23.0 ± 1.9% (mean ± SD) of the administered dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared to urine. Bryostatin 1 was widely distributed in many organs but concentrated in the lung, liver, gastrointestinal tract, and fatty tissue. The concentration in the gastrointestinal tract, along with the fecal excretion, suggests the possibility of enterohepatic circulation of this drug. In summary, this study demonstrates that Bryostatin 1 is relatively stable in vivo , widely distributed but concentrated in some major tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful in the design of future human trials with this anticancer drug.