Bryostatin 1

Bryostatin 1 is an activator of protein kinase C (PKC) [1].

PKC is a monomeric Ca2+- and phospholipid-dependent Ser/Thr protein kinase and plays an important role in growth factor-activated signaling and malignant transformation.

Bryostatin 1 is a PKC activator. In 3T3 cells, bryostatin 1 stimulated ornithine decarboxylase (ODC) activity in a dose-dependent way [1]. In HL-60 cells, bryostatin 1 induced protein kinase C translocated from the cytosolic to membrane. Bryostatin 1 (10 nM) induced monocytic differentiation and partially inhibited proliferation. Also, bryostatin 1 (10 nM) reduced the expression of c-myc and induced c-fos, c-fms and tumor necrosis factor transcripts [2].

In SENCAR mouse, bryostatin 1 caused [3H]TdR incorporation into epidermal DNA and induced epidermal hyperplasia in a dose-dependent way. Also, bryostatin 1 stimulated alkaline phosphatase activity in the epidermis and significantly reduced the tumor incidence [1]. In a B16 melanoma pulmonary metastases mice model, bryostatin 1 significantly reduced the number of lung nodules. Bryostatin 1 inhibited the generation of interleukin 2 by lymphokine-activated killer cells and also inhibited natural killer cell activity [3].

References:
[1].  Gschwendt M, Fürstenberger G, Rose-John S, et al. Bryostatin 1, an activator of protein kinase C, mimics as well as inhibits biological effects of the phorbol ester TPA in vivo and in vitro. Carcinogenesis, 1988, 9(4): 555-562.
[2].  Stone RM, Sariban E, Pettit GR, et al. Bryostatin 1 activates protein kinase C and induces monocytic differentiation of HL-60 cells. Blood, 1988, 72(1): 208-213.
[3].  Schuchter LM, Esa AH, May S, et al. Successful treatment of murine melanoma with bryostatin 1. Cancer Res, 1991, 51(2): 682-687.

Effects of exercise and bryostatin-1 on serotonin dynamics after cerebral infarction.[Pubmed:27128726]

Neuroreport. 2016 Jun 15;27(9):659-64.

Although it has been suggested that the combination of exercise and bryostatin-1 administration may induce greater functional recovery than exercise alone, the detailed molecular mechanisms are not well known. Here, we examined the relationship between this combination treatment and monoamine dynamics in the cerebral cortex peri-infarction area to promote our understanding of these molecular mechanisms. Experimental cerebral cortex infarctions were produced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Monoamine concentrations in the perilesional cortex were analyzed by high-performance liquid chromatography. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. Moreover, performance in the rotarod test after the combination of exercise and bryostatin-1 administration was significantly greater than that after exercise alone. In the analysis of monoamines, serotonin (5-HT) concentrations were significantly higher in the groups treated with exercise and bryostatin-1. In addition, 5-HT turnover was significantly lower in the groups treated with exercise and bryostatin-1. Furthermore, the mean latency in the rotarod test showed a significant positive correlation with 5-HT levels. In immunohistochemical analysis, 5-HT immunoreactivity in the dorsal raphe nucleus was shown to be higher in the groups treated with exercise. In the present study, we detected changes in the levels of monoamines associated with the combined treatment of exercise and bryostatin-1 administration in the perilesional cortex. It has been suggested that this combination of therapies may affect 5-HT turnover and serve to increase local 5-HT concentrations in the perilesional area.

Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy.[Pubmed:26891037]

AIDS. 2016 Jun 1;30(9):1385-92.

OBJECTIVE: The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA remains to be proven in treated HIV-1-infected patients. METHODS: In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 mug/m) compared with placebo. RESULTS: Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 mug/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 mug/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 mug/m arm. CONCLUSION: Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.

HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration.[Pubmed:27994072]

J Immunol. 2017 Feb 1;198(3):1229-1241.

A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4(+) and CD8(+) T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB.

Isolation, analytical measurements, and cell line studies of the iron-bryostatin-1 complex.[Pubmed:27068183]

Bioorg Med Chem Lett. 2016 May 15;26(10):2489-2497.

Bryostatin-1 is a marine natural product that has demonstrated medicinal activity in pre-clinical and clinical trials for the treatment of cancer, Alzheimer's disease, effects of stroke, and HIV. In this study, iron-bryostatin-1 was obtained using a pharmaceutical aquaculture technique developed by our lab that cultivates marine bacteria for marine natural product extraction. Analytical measurements (1)H and (13)C NMR, mass spectrometry, and flame atomic absorption were utilized to confirm the presence of an iron-bryostatin-1 complex. The iron-bryostatin-1 complex produced was then tested against the National Cancer Institute's 60 cell line panel. Adding iron to bryostatin-1 lowered the anti-cancer efficacy of the compound.

Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice.[Pubmed:24659806]

J Pharmacol Exp Ther. 2014 Jun;349(3):393-401.

Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder that currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase epsilon activator with pharmacological profiles of rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Long-term treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor expression and secretion, postsynaptic density-95 levels, glycogen synthase kinase-3beta phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacologic treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.

Bryostatin-1: pharmacology and therapeutic potential as a CNS drug.[Pubmed:16834754]

CNS Drug Rev. 2006 Spring;12(1):1-8.

Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.

The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1.[Pubmed:9618462]

Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6624-9.

The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of Bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with Ki = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

The catalytic domain of protein kinase Cdelta confers protection from down-regulation induced by bryostatin 1.[Pubmed:9407126]

J Biol Chem. 1997 Dec 26;272(52):33338-43.

Bryostatin 1 (Bryo) has been shown to induce biphasic dose-response curves for down-regulating protein kinase Cdelta (PKCdelta) as well as for protecting PKCdelta from down-regulation induced by phorbol 12-myristate 13-acetate (PMA). To identify regions within PKCdelta that confer these responses to Bryo, we utilized reciprocal PKCalpha and PKCdelta chimeras (PKCalpha/delta and PKCdelta/alpha) constructed by exchanging the regulatory and catalytic domains of these PKCs. These chimeras and wild-type PKCalpha/alpha and PKCdelta/delta constructed in the same way were stably expressed in NIH 3T3 fibroblasts. Twenty-four h of treatment with Bryo induced a biphasic dose-response curve for down-regulating both wild-type PKCdelta/delta and the PKCalpha/delta chimera. In contrast, Bryo led to a nearly complete down-regulation of both PKCalpha/alpha and PKCdelta/alpha and also produced a faster mobility form of these species on SDS-polyacrylamide gel electrophoresis. The nature of both the regulatory and, to a lesser extent, the catalytic domains affected the potency of Bryo to down-regulate the chimeric PKC proteins as well as to protect PKCalpha/delta and PKCdelta/delta from down-regulation. Bryo at high concentrations also inhibited the down-regulation of PKCdelta/delta and PKCalpha/delta induced by 1 microM PMA when co-applied. The portion of PKC protected by Bryo from down-regulation by either Bryo or PMA was localized in the particulate fraction of the cells. We conclude that the catalytic domain of PKCdelta confers protection from down-regulation induced by Bryo or Bryo plus PMA, suggesting that this domain contains the isotype-specific determinants involved in the unique effect of Bryo on PKCdelta.

Bryostatin 1 is a natural macrolide isolated from the bryozoan Bugula neritina and is a potent and central nervous system (CNS)-permeable PKC modulator. Bryostatin 1 binds to the isolated C1 domain of Munc13-1 and the full-length Munc13-1 protein with Kis of 8.07 nM and 0.45 nM, respectively. Bryostatin 1 has anti-cancer, anti-inflammatory, neuroprotective, anti-HIV-1 infection properties.

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