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-α (TNFα) strongly increased the IL-8 and MCP-1 secretion of NB-4 cells. Several staurosporine analogues clearly inhibited the TPA-induced but enhanced the TNFα-mediated chemokine increase. These effects, namely the increase of chemokines in untreated or TNFα-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.