Bryostatin-5 Blocks Stromal Cell–Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors

Abstract

The chemokine receptor CXCR4 and its ligand, stromal cellderived factor-1 (SDF-1), play important roles in hematopoiesis regulation, lymphocyte activation, and trafficking, as well as in developmental processes, including organogenesis, vascularization, and embryogenesis. The receptor is also involved in HIV infection and tumor growth and metastasis. Antagonists of CXCR4 have been widely evaluated for drugs against HIV and tumors. In an effort to identify novel CXCR4 antagonists, we screened a small library of compounds derived from marine organisms and found bryostatin-5, which potently inhibits chemotaxis induced by SDF-1 in Jurkat cells. Bryostatin-5 is a member of the macrolactones, and its analogue bryostatin-1 is currently being evaluated in clinical trials for its chemotherapeutic potential. The involvement of bryostatins in the SDF-1/CXCR4 signaling process has never been reported. In this study, we found that bryostatin-5 potently inhibits SDF-1-induced chemotaxis but does not affect serum-induced chemotaxis. Further studies indicate that this inhibitory effect is not due to receptor antagonism but rather to bryostatin-5-induced receptor desensitization and down-regulation of cell surface CXCR4. We also show that these effects are mediated by the activation of conventional protein kinase C. [Cancer Res 2008;68(21):8678-86]

Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

“…This latent viral reactivation component is essential along with HAART to purge the virus from compartmentalized latent viral reservoirs. Latent HIV responds to T-cell activation signals [9]–[15]. T-cell activation strategies include treatment with proinflammatory cytokines such as IL-6, TNF-α, IL-2, and in monocyte/macrophages IFN-γ.…”

“…Bryostatin also causes dephosphorylation of CDK2 which inhibits RNA polymerase-II phosphorylation [42], thus impairing HIV Tat function [43]. Bryostatin-5 has been reported to block stromal cell derived factor-1 (SDF-1), a natural ligand of CXCR4 receptors [9].…”

Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator

“…Bryostatin, a macrocyclic lactone isolated from endosymbiont γ-proteobacterial Endobugula sertula [42], is an activator of protein kinase C (PKC) and has been shown to have diverse biological activities. Recently, we and others have shown that bryostatin has anti-HIV-1 activity via various mechanisms, such as blocking the effect of stromal-cell-derived factor-1 (SDF-1), which it does by down regulating its CXCR4 receptors [43] or modulating CD4 and CXCR4 receptors [44,45]. Bryostatin is currently being used in a phase I clinical trial in patients with nonhematologic tumors, and in a phase II trial for relapsed multiple myeloma [46,47].…”

Am80 inhibits stromal cell-derived factor-1-induced chemotaxis in T-cell acute lymphoblastic leukemia cells

“…These results indicate that Am80induced acceleration of CXCR4 internalization might occur via activation of the conventional PKC. He et al reported that bryostatin-5, isolated from marine organisms, inhibited CXCR4 expression and SDF-1-induced chemotaxis via activation of conventional PKC [24]. They also reported that GF109203X, an inhibitor of conventional and novel PKCs, but not rotterin, a selective inhibitor of the novel PKC isoform PKC d, reversed bryostatin-5induced acceleration of CXCR4 internalization.…”