Differentiation and Growth Modulation of Myeloid Leukemia Cells by the Protein Kinase C Activating Agent Bryostatin-1

Abstract

Bryostatin-1 (Bryo), a macrocyclic lactone of the sea water bryozoan Bugula neritina, is a potent activator of protein kinase C and was found to exhibit antineoplastic activity in several systems. We studied the effect of Bryo on differentiation and growth modulation of human myeloid leukemia cell lines and freshly explanted blood cells from patients with myeloid leukemia. Alterations at the molecular level and phenotypic changes triggered by Bryo were similar, but not identical, to those induced by phorbol esters. Bryo was able to inhibit cellular proliferation as evidenced by [³H]-thymidine uptake and induced morphological changes associated with monocytic differentiation. In studies using continuous cell lines, the glucocorticoid dexamethasone was unable to prevent the Bryo-induced growth inhibition or the induced phenotypic changes. However, in fresh myeloid Blood cells dexamethasone attenuated these Bryo-triggered effects. Our own data taken together with reports from the literature reviewed here suggest the following conclusions: (i) Bryo, while lacking tumor promoting activity, is able to induce differentiation in maturation arrested leukemia cells; (ii) it exhibits selective antiproliferative properties in normal or malignant hematopoietic cells and supports growth of multipotent stem cells. These features might qualify Bryostatin-1 as a potential candidate for promising research and possibly for future clinical applications.

Key Words:

• Myeloid leukemia
• cell lines
• proliferation
• differentiation
• Bryostatin
• Protein kinase C