A potent Protein Kinase C modulator isolated from the bryozoan Bugula neritina
Bryostatin 1 is one of a series of cyclic macrolides isolated from the marine bryozoan Bugula neritina (Order Cheilostomata). This arborescent bryozoan is found in temperate and subtropical environments worldwide, but only B. neritina from California and the Gulf of Mexico is known to contain Bryostatins 1, 2 and 3 that are characterized by the C- 20 (E,E)-octa-2-dienoate ester (Pettit, 1985)
Bryostatin 1, a macrolide lactone, was first isolated from the bryozoan Bugula neritina by Pettit et al. (1985) and recently postulated to be produced by a bacterial symbiont of the bryozoan (Davidson et al., 2001).
Schaufelberger et al. (1991) reported a novel scheme for the large-scale isolation of bryostatin from the bryozoan Bugula neritina. The reported procedure consists of several organic phase extraction and chromatographic purification steps.
Aphios (Castor, 1995, 1997, 1998, 2001) has improved the isolation of Bryostatin 1 from Bugula neritina utilizing near-critical and supercritical fluids as an alternate to conventional organic solvents techniques which are time consuming, labor intensive and environmentally insensitive even at a laboratory scale.
Bryostatin 1 has undergone several Phase I and Phase II clinical trials against melanomas, lymphomas and renal cancers by the National Cancer Institute in the United States and by the Cancer Research Campaign in Great Britain (Newman, 1995; Philip et al., 1993; and Prendiville et al., 1993; Clamp et al., 2002; Zonder et al., 1999; Varterasian et al., 2000).
In vitro studies have shown that Bryostatin 1 is a potent antileukemic agent that works by a unique and unusual mechanism. This compound exhibits selective activity against leukemias and directly stimulates bone marrow progenitor cells to form colonies that functionally activate neutrophils (Suffness et al., 1989). This combined activity is unusual because most cytotoxic anticancer agents are toxic to bone marrow. The mechanism of activity is unknown but it may be related to the ability of the bryostatins to modulate the protein kinase C receptor.
Bryostatin 1 exhibits a high affinity for PKC and displaces phorbol esters from PKC at low nano- to picomolar levels (Hennings et al., 1987; Mutter et al., 2000). Many other biological effects have also been shown at the subnanomolar level. The established lack of tumor promotion and the fact that Bryostatin 1 is already in clinical development as a tumor suppressor has prompted exploration of its use as a modifier of APP metabolism and its capacity to enhance cognition, both effects that appear to be mediated by PKC activation (Etcheberrigaray et al., 2004; Olds et al., 1993; Favit et al., 1998; Alkon et al., 2005).
Bryostatin 1 activates HIV-1 gene replication through an NF-κB-dependent pathway in chronically infected macrophage cell lines (Qatsha et al., 1993; Vlach and Pitha 1992), and downregulates the expression of CD4 in T cell lines (Boto et al., 1991). Indeed, reactivation of HIV-1 latency in T and other lymphoid cells requires cell activation and it has been demonstrated that Bryostatin 1 activates resting humans' T cells (Trenn et al., 1988) and enhances the maturation of human dendritic cells through a PKC-dependent pathway (Do et al., 2004).
Using Jurkat-LAT-GFP cells, a tractable model of HIV-1 latency, we have found that Bryostatin 1 reactivates HIV-1 through a classical PKC-dependent pathway. In addition, Bryostatin 1 downregulates the expression of the HIV-1 co-receptors CD4 and CXCR4 and prevents de novo HIV-1 infection in susceptible cells (Pérez et al., 2010).
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