Bryostatins trigger human polymorphonuclear neutrophil and monocyte oxidative metabolism: association with in vitro antineoplastic activity.
Bryostatin-1-but not bryostatin-13-a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, triggered human polymorphonuclear neutrophil (PMN) and monocyte release of reactive oxygen radicals, as measured by the generation of lucigenin chemiluminescence and by the ferricytochrome c reduction assay. The release of oxygen radicals by bryostatins was sensitive to inhibitors of protein kinases, but resistant to the inhibition of phospholipase A2 activity and arachidonic acid metabolism (prior treatment with mepacrine or indomethacin). Comparison of the effect of protein kinase (PK) inhibitors H-8, H-7 and staurosporine on bryostatin-1-induced neutrophil oxygen radical release further suggested a requirement for activation of phospholipid-dependent PKC, but not for cGMP- or cAMP-dependent PK. In cytostatic assays, PMNs treated with bryostatin-1 inhibited the growth of the erythroleukaemic cell line K562 in a concentration-dependent manner. These findings suggest that the reported antineoplastic effect of bryostatins may result at least in part from activation of PMNs and monocytes.
Esa
A H
AH
Département d'Immunologie, Unité d'Immunophysiologie moléculaire, Institut Pasteur, Paris, France.
Warren
J T
JT
Hess
A D
AD
May
W S
WS
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D054713:Bryostatins; D002013:Bryozoa; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology*; D008163:Luminescent Measurements; D018942:Macrolides; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019311:Staurosporine; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000970:Antineoplastic Agents; D054713:Bryostatins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D007783:Lactones; D018942:Macrolides; D010879:Piperazines; D017382:Reactive Oxygen Species; D013481:Superoxides; C046785:bryostatin 1; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate