Modulation of ara-C induced apoptosis in leukemia by the PKC activator bryostatin 1.
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
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Division of hermatology , Department of Pharmacology and Microbiology , Medical College of Virginia, Richmond, VA 23298, USA. stgrant@vgems.vcu.edu
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D054713:Bryostatins; D002454:Cell Differentiation; D003561:Cytarabine / Q000494:pharmacology*; D004347:Drug Interactions; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D054713:Bryostatins; C000715470:MAS1 protein, human; D018942:Macrolides; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; C046785:bryostatin 1