Biological activity of 26-succinylbryostatin 1

• Published in: Biochimica et biophysica acta 1996-07, Vol.1312 (3), p.197-206
• Main Authors: Bignami, Gary S., Wagner, Fred, Grothaus, Paul G., Rustagi, Pradip, Davis, Dana E., Kraft, Andrew S.
• Format: Article
• Language: English
• Subjects: 26-Succinylbryostatin 1; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Blood Platelets - drug effects; Blood Platelets - physiology; Blotting, Western; Bryostatins; Cell Line; Cell Membrane - enzymology; Chloramphenicol O-Acetyltransferase - metabolism; Enzyme Activation; Glutathione Transferase; Humans; Kinetics; Lactones - chemical synthesis; Lactones - pharmacology; Lactones - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Macrolides; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Mice; Mice, Inbred C3H; Phorbol 12,13-Dibutyrate - metabolism; PKC; PKC translocation; Platelet Aggregation - drug effects; Protein Kinase C - metabolism; Recombinant Fusion Proteins - metabolism; Tumor Cells, Cultured
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/0167-4889(96)00018-3

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-I into mice carrying B 16 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.