[Frontiers in Bioscience 2, d232-241, June 1, 1997]
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MODULATION OF ARA-C INDUCED APOPTOSIS IN LEUKAMAIA BY THE PKC ACTIVATOR BRYOSTATIN 1

Steven Grant.

Division of hermatology , Department of Pharmacology and Microbiology , Medical College of Virginia

Received 5/23/97; Accepted 5/28/97

4. BRYOSTATIN 1

Bryostatin 1 is a macrocyclic lactone derived from the marine organism Bugula neritina (34). It was initially identified in the NCI's marine product discovery program, and was found to have activity against a variety of hematopoietic and non-hematopoietic tumor cells both in vitro and in vivo (35-38). Based upon this activity, several phase I trials of bryostatin 1 in humans have been completed (39-41), and phase II trials are currently underway.

Bryostatin 1 shares several features with tumor-promoting phorbols such as phorbol 12-myristate 13-acetate (PMA) in that it binds to and activates protein kinase C, thereby inducing enzyme translocation to membrane and nucleus (42). The actions of bryostatin 1, like those of PMA, are synergistically enhanced by agents like calcium ionophore (A23187) which increase the availability of intracellular calcium ((Ca2+)i) (43). In this way, A23187 mimics activation of phospholipase C, which results in generation of IP3 and liberation of (Ca2+)i. However, bryostatin 1 exhibits a different spectrum of activity from the phorbols, and in fact blocks certain phorbol-associated actions that it does not share, including tumor promotion (44) and induction of leukemic cell differentiation (45). The unique characteristics of bryostatin 1 may stem from specific patterns of PKC isoform activation (46) or nuclear translocation (47). Alternatively, they may result from bryostatin 1's capacity to induce profound PKC down-regulation (48), a consequence of enzyme ubiquitinization and proteasomal degradation (49).

Bryostatin 1 has been shown to exert pleiotropic effects on leukemic cell differentiation. For example, bryostatin 1 induces maturation in some human promyelocytic leukemic (HL-60) sublines, but not others (50,51). Bryostatin 1 may also trigger a differentiation program in the human monocytic leukemia cell line U937, but its actions are considerably weaker than those of PMA (52). Against primary human leukemic cell cultures, bryostatin 1 inhibits both clonogenicity and self-renewal capacity (53,54). In contrast to inhibitory effects toward leukemic cells, bryostatin 1 stimulates the in vitro growth of normal hematopoietic progenitors (55,56), although accessory cell actions have been invoked to account for this effect (57). The basis for bryostatin 1's antileukemic selectivity remains to be established.