Differential effects of staurosporine and its analogues on chemokine release by promyelocytic leukemia cell line NB-4.
The protein kinase inhibitor staurosporine elicits multiple responses in various systems. We evaluated nine naturally occurring staurosporine derivatives as modulators of chemokine production by monitoring the secretion of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) in the cell line NB-4. Several staurosporines increased, dose- and time-dependently, the IL-8 and MCP-1 concentration in the cell culture supernatants and three derivatives strongly inhibited proliferation of the NB-4 cells. By comparing the efficiency of these analogues at the same concentration, the lead compound staurosporine (STS-1) was the best inducer of chemokine secretion, whereas 3-hydroxystaurosporine (STS-3) was the most potent growth inhibitor. Besides the staurosporines, also 12-O-tetradecanoyl phorbol acetate (TPA) and tumor necrosis factor-alpha (TNFalpha) strongly increased the IL-8 and MCP-1 secretion of NB-4 cells. Several staurosporine analogues clearly inhibited the TPA-induced but enhanced the TNFalpha-mediated chemokine increase. These effects, namely the increase of chemokines in untreated or TNFalpha-treated cells and the inhibition of chemokine release in TPA-treated cells, cannot be explained by the exclusive inhibition of protein kinase C (PKC). It may indicate that staurosporines are additionally involved in activation of the PKC-triggered chemokine production.
Steube
Klaus G
KG
DSMZ, German Collection of Microorganisms and Cell Cultures, Mascheroder Weg 1B, 38124 Braunschweig, Germany. kst@dsmz.de
Meyer
Corinna
C
Schupp
Peter
P
Proksch
Peter
P
Drexler
Hans G
HG
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018932:Chemokine CCL2; D018925:Chemokines; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D019311:Staurosporine