Inhibition of phospholipid signalling and proliferation of Swiss 3T3 cells by the wortmannin analogue demethoxyviridin.
Growth factors and certain oncogenes activate a range of phospholipid-mediated signal transduction pathways resulting in cell proliferation. Demethoxyviridin (DMV), a structural analogue of wortmannin and recently reported as a potent inhibitor of phosphoinositide-3-kinase, inhibited bombesin plus insulin-stimulated increase in cell number in Swiss 3T3 cells, a model of cell proliferation. The drug produced cytostatic effects at concentrations below 1 microM and cytotoxic effects at 10 microM. In intact Swiss 3T3 cells DMV inhibited insulin-stimulated PI 3- and 4-kinases and bombesin-stimulated phospholipases C, D and A2 in the nanomolar range. DMV also inhibited bombesin-stimulated tyrosine phosphorylation of a range of proteins at nM concentrations. This study shows that DMV inhibited multiple stimulated signalling pathways which lead to increased Swiss 3T3 cell proliferation. A stable analogue of DMV may have chemotherapeutic potential.
Cross
M J
MJ
Institute for Cancer Studies, University of Birmingham Medical School, Edgbaston, UK.
Hodgkin
M N
MN
Plumb
J A
JA
Brunton
V G
VG
Stewart
A
A
MacAully
G
G
Hill
R
R
Kerr
D J
DJ
Workman
P
P
Wakelam
M J
MJ
D016475:3T3 Cells; D000730:Androstadienes; D000736:Androstenes / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010740:Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010743:Phospholipids / Q000502:physiology*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D000736:Androstenes; D004791:Enzyme Inhibitors; D007328:Insulin; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids; D014443:Tyrosine; C070594:demethoxyviridin; D020794:Receptor Protein-Tyrosine Kinases; D010740:Phospholipases; D001839:Bombesin; D000077191:Wortmannin