Biological activity of 26-succinylbryostatin 1.

Bryostatin 1, a macrocyclic lactone, has undergone phase I trials as an anticancer agent. Because of the lipid solubility of this compound it must be delivered either in ethanol or in a PET formulation. During the trial, these vehicles caused a large number of treatment-related side effects. We have synthesized the triethanolamine salt of 26-succinylbryostatin 1 and find that this compound is approx. 100-fold more water soluble than bryostatin 1. Because of the potential for clinical use, we have evaluated the biologic activity of this compound. We find that in a concentration-dependent manner 26-succinylbryostatin 1 is capable of activating protein kinase C (PKC) in vitro and displacing [3H]PDBu from PKC. However, at all concentrations tested the activity was less than the parent compound bryostatin 1. Addition of bryostatin 1 but not 26-succinylbryostatin 1 to U937 leukemic cells in culture stimulated a drop in cytosolic PKC, secondary to translocation of PKC to the membrane. Although 26-succinylbryostatin 1 did not stimulate a drop in the cytosolic levels of PKC, addition to U937 cells activated transcription from an AP-1 enhancer construct and c-Jun protein phosphorylation in a similar fashion to bryostatin 1 and differentiation of U937 cells. Unlike bryostatin 1, 26-succinylbryostatin 1 was unable to cause aggregation of human platelets. Although injection of bryostatin-1 into mice carrying B16 melanoma inhibits tumor growth, there was no significant inhibition of melanoma growth when identical doses of 26-succinylbryostatin 1 were injected. Therefore, 26-succinylbryostatin 1 shares some but not all of the pharmacologic properities of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.
AuthorsG S Bignami, F Wagner, P G Grothaus, P Rustagi, D E Davis, A S Kraft
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1312 Issue 3 Pg. 197-206 (Jul 24 1996) ISSN: 0006-3002 [Print] NETHERLANDS
PMID8703988 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 26-succinylbryostatin 1
  • Antineoplastic Agents
  • Bryostatins
  • Lactones
  • Macrolides
  • Recombinant Fusion Proteins
  • Phorbol 12,13-Dibutyrate
  • bryostatin 1
  • Chloramphenicol O-Acetyltransferase
  • Glutathione Transferase
  • Protein Kinase C
  • Animals
  • Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
  • Blood Platelets (drug effects, physiology)
  • Blotting, Western
  • Bryostatins
  • Cell Line
  • Cell Membrane (enzymology)
  • Chloramphenicol O-Acetyltransferase (metabolism)
  • Enzyme Activation
  • Glutathione Transferase
  • Humans
  • Kinetics
  • Lactones (chemical synthesis, pharmacology, therapeutic use)
  • Lung Neoplasms (drug therapy, pathology, secondary)
  • Macrolides
  • Melanoma, Experimental (drug therapy, pathology)
  • Mice
  • Mice, Inbred C3H
  • Phorbol 12,13-Dibutyrate (metabolism)
  • Platelet Aggregation (drug effects)
  • Protein Kinase C (metabolism)
  • Recombinant Fusion Proteins (metabolism)
  • Tumor Cells, Cultured

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