Chemistry and clinical biology of the bryostatins

Mutter, Roger; Wills, Martin

doi:10.1016/s0968-0896(00)00150-4

Cited by 175 publications

(101 citation statements)

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“…It has already been established that ␣ and play a role in APP processing (18,34). It is also known that the ␦-isoform may be the key for the anticancer properties of bryostatin (41,57). However, it remains unclear whether its activation and the activation of ␤ (translocation) played a role in the enhanced ␣-secretase processing of APP in fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice

Etcheberrigaray

Tan

Dewachter

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

313

190

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Alzheimer's disease (AD) characteristically presents with early memory loss. Regulation of K ؉ channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative memory which are also altered or defective in AD. PKC is also involved in the processing of the amyloid precursor protein (APP), a central element in AD pathophysiology. In previous studies, we demonstrated that benzolactam (BL), a novel PKC activator, reversed K ؉ channels defects and enhanced secretion of APP␣ in AD cells. In this study we present data showing that another PKC activator, bryostatin 1, at subnanomolar concentrations dramatically enhances the secretion of the ␣-secretase product sAPP␣ in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP␣ and reduced A␤40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain A␤40 and A␤42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment, thus offering a promising target for drug development. Because bryostatin 1 is devoid of tumor-promoting activity and is undergoing numerous clinical studies for cancer treatment in humans, it might be readily tested in patients as a potential therapeutic agent for Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

“…Novel PKC activators (18,23,39) may offer an alternative, but their safety for eventual human use remains to be demonstrated. A compound that activates PKC and lacks tumor-promoting activity is the natural product bryostatin 1 (40,41). Bryostatin is being actively investigated in humans (phases I and II) as an anticancer agent (42,43).…”

mentioning

confidence: 99%

Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice

Etcheberrigaray

Tan

Dewachter

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

313

190

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“…It should be, however, mentioned here that modulation of PKC activity may not be the only biological action of bryostatins (25). For example, in B16/F10 melanoma cells (26) epi-bryostatin-1, a bryostatin-1 stereoisomer, with much lower affinity for PKC, exhibits the same potency in inhibiting cell growth as bryostatin-1 (41), suggesting the involvement of aPKC activity-independent action. Nevertheless, modulation of PKC activity is the only well established biological mechanism by which bryostatin-1 produces a variety of biological effects.…”

Section: Pharmacodynamicsmentioning

confidence: 91%

Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug

Sun

Alkon

2006

CNS Drug Reviews

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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.

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“…A similar result was observed during a screening at the National Cancer Institute (Garson, 1994). Bryostatins are the best known examples of a bryozoan secondary metabolites with potent cytotoxic activities, of which bryostatin 1 is currently in clinical trials (Pettit, 1991;Mutter and Wills, 2000;Hale et al, 2002).…”

Section: Bryozoans and Cnidariamentioning

confidence: 99%