Biological activity of 26-succinylbryostatin 1

Gary S. Bignami, Fred Wagner, Paul G. Grothaus, Pradip Rustagi, Dana E. Davis, Andrew Kraft

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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 properties of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalBBA - Molecular Cell Research
Volume1312
Issue number3
DOIs
Publication statusPublished - Jul 24 1996
Externally publishedYes

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Keywords

  • 26-Succinylbryostatin 1
  • Antitumor activity
  • PKC
  • PKC translocation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biophysics

Cite this

Bignami, G. S., Wagner, F., Grothaus, P. G., Rustagi, P., Davis, D. E., & Kraft, A. (1996). Biological activity of 26-succinylbryostatin 1. BBA - Molecular Cell Research, 1312(3), 197-206. https://doi.org/10.1016/0167-4889(96)00018-3