WORTMANNIN AND ITS STRUCTURAL ANALOG DEMETHOXYVIRIDIN INHIBIT STIMULATED PHOSPHOLIPASE A(2) ACTIVITY IN SWISS 3T3 CELLS - WORTMANNIN IS NOT A SPECIFIC INHIBITOR OF PHOSPHATIDYLINOSITOL 3-KINASE

Wortmannin and its structural analogue demethoxy-viridin (DMV) have been reported to be specific inhibitors of phosphatidylinositol 3-kinase activity. Here we report that these compounds are not as selective as assumed and demonstrate inhibition of bombesin stimulated phospholipase A(2) activity by both wortmannin and DMV with an IC50 (2 nM) which is slightly more potent than the inhibition of insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate generation in these cells (similar to 10 nM). While it has not been possible to fully block in vitro phospholipase A(2) activity with wortmannin, inhibition cannot be a consequence of inhibition of PI 3-kinase activity since bombesin fails to generate 3-phosphorylated lipids in the intact cell. Therefore, while wortmannin is indeed a PI S-kinase inhibitor, it is not as specific as previously reported, and experimental conclusions based solely on its use should be treated with caution.