|[Frontiers in Bioscience 2, d232-241, June 1, 1997]|
MODULATION OF ARA-C INDUCED APOPTOSIS IN LEUKAMAIA BY THE PKC ACTIVATOR BRYOSTATIN 1|
Division of hermatology , Department of Pharmacology and Microbiology , Medical College of Virginia
Received 5/23/97; Accepted 5/28/97
The macrocyclic lactone PKC activator bryostatin 1 represents a member of class of antineoplastic agents that exert their antitumor, immunomodulatory, and chemomodulatory actions through induction of perturbations in intracellular signalling pathways. There is now accumulating evidence that bryostatin 1 increases the susceptibility of myeloid leukemia cells to ara-C-mediated apoptosis, an event that is both dose- and sequence-dependent. This phenomenenon may involve multiple mechanisms, including alterations in ara-C metabolism, activation of specific PKC isoforms, down-regulation of PKC activity, induction of imabalances between stress- and survival -related signalling pathways, dysregulation of cell cycle-related genes (e.g., c-Myc), and phosphorylation of Bcl-2. A summary of these interactions is illustrated in Figure 1. An improved understanding of the mechanisms by which agents such as bryostatin 1 lower the threshold for cytotoxic drug-mediated apoptosis in leukemia may provide a rationale framework for the design of entirely novel chemotherapeutic regimens in the treatment of both hematologic and non-hematologic malignancies.
Figure 1 Summary of potential interactions between bryostatin 1 (Bry) and ara-C in relation to leukemic cell death. (1) Under some circumstances, bryostatin 1 may augment ara-C conversion to ara-CTP; (2) Chronic exposure to bryostatin 1 down-regulates PKC activity, thereby reducing its presumed cytoprotective effects; (3) Bryostatin 1 may phosphorylate Bcl-2, potentially antagonizing its anti-apoptotic actions; (4) Bryostatin 1 may augment ara-C's lethal actions by permitting continued expression of c-Myc; (5) Induction of leukemic cell differentiation in susceptible cells by bryostatin 1 prior to ara-C administration precludes potentiation of apoptosis; (6) In contrast, induction of differentiation by bryostatin 1 after ara-C promotes this process.