Peripheral blood cells from nine patients with B-
chronic lymphocytic leukemia (B-CLL) were treated in vitro with
bryostatin 1 (a macrocyclic
lactone derived from a marine invertebrate). Like the
phorbol ester 12-0-tetradecanoyl-phorbol 13-acetate (TPA),
bryostatin 1 activates
protein kinase C (PKC), which plays a central role in the
phosphatidylinositol signal transduction pathway. The effects of
bryostatin 1 alone and in combination with TPA or with the
calcium mobilizing
ionophore A23187 were assessed by morphological appearance, cell adherence and aggregation,
RNA and
DNA synthesis, and
immunoglobulin (Ig) production. While eight of nine B-CLL cultures remained proliferatively inert,
bryostatin 1 could effectively trigger activation and differentiation of B-CLL cells in all cases as inferred by the induction of morphological changes,
RNA synthesis, and monotypic Ig production. Addition of
calcium ionophore A23187 to
bryostatin 1-exposed cells resulted in significantly increased values for
RNA synthesis and Ig production and in the acquisition of plasmacytoid morphology.
Bryostatin 1 and the dual signal of
bryostatin 1 plus
A23187 mimicked the stimulatory action of TPA and the combination of TPA plus
A23187, respectively. Overall,
bryostatin 1 was less active than equivalent concentrations of TPA. This lesser efficacy may, however, reflect a quantitative rather than qualitative difference.
Bryostatin 1 partially antagonized TPA-mediated effects on B-CLL cells suggesting different modes of action by the two activators. These studies indicate that
bryostatin 1 has effective differentiation-inducing properties on B-CLL cells that can differentiation-inducing properties on B-CLL cells that can be accentuated by a
calcium ionophore.