Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. Wortmannin is not a specific inhibitor of phosphatidylinositol 3-kinase.
Wortmannin and its structural analogue demethoxyviridin (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 A2 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 (approximately 10nM). While it has not been possible to fully block in vitro phospholipase A2 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 3-kinase inhibitor, it is not as specific as previously reported, and experimental conclusions based solely on its use should be treated with caution.
Cross
M J
MJ
Institute for Cancer Studies, University of Birmingham, United Kingdom.
Stewart
A
A
Hodgkin
M N
MN
Kerr
D J
DJ
Wakelam
M J
MJ
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates / Q000032:analysis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D010740:Phospholipases; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D000077191:Wortmannin
D000730:Androstadienes; D000736:Androstenes; D018129:Phosphatidylinositol Phosphates; D010726:Phosphodiesterase Inhibitors; C060974:phosphatidylinositol 3,4,5-triphosphate; C070594:demethoxyviridin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D010739:Phospholipase D; D001839:Bombesin; D000077191:Wortmannin