|[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
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.