Open Access
Article

Modulation of ara-C induced apoptosis in leukemia by the PKC activator bryostatin 1

Steven Grant1,*
1
Division of hermatology , Department of Pharmacology and Microbiology , Medical College of Virginia, USA
DOI: 10.2741/A187 Volume 2 Issue 4, pp.242-252
Published: 01 June 1997
*Corresponding Author(s):  
Steven Grant
E-mail:  
stgrant@vgems.vcu.edu
Abstract

Modulation of ara-C-induced apoptosis in human leukemia cells by the macrocyclic lactone PKC activator bryostatin 1 occurs at multiple levels, and involves a variety of oncogenes and signalling pathways. Under some circumstances, bryostatin 1 may lead to enhanced conversion of ara-C to its lethal metabolite, ara-CTP. However, bryostatin 1 is able to potentiate ara-C-mediated cytotoxicity in the absence of metabolic perturbations, presumably by modulating the cell death pathway itself. For example, chronic exposure of cells to bryostatin 1 leads to PKC down-regulation, which may alter the balance between survival (e.g., ERK) versus stress (e.g., SAPK/JNK)-related pathways. The ability of bryostatin 1 to enhance ara-C-mediated apoptosis is inversely related to its capacity to induce leukemic cell maturation and may involve the failure to down-regulate expression of the cell cycle progression-related proto-oncogene, c-myc. Finally, recent evidence suggests that bryostatin 1 may act, through modification of Bcl-2 phosphorylation status, at a distal site in the cell death pathway. These studies could provide a paradigm important for understanding the mechanism(s) by which agents acting through signal transduction pathways modulate cytotoxic drug-induced cell death.

Key words

apoptosis, ara-c, bryostatin 1, leukamia, PKC

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Steven Grant. Modulation of ara-C induced apoptosis in leukemia by the PKC activator bryostatin 1. Frontiers in Bioscience-Landmark. 1997. 2(4); 242-252.