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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.

Original publication

DOI

10.1016/s0925-4439(97)00053-7

Type

Journal article

Journal

Biochim Biophys Acta

Publication Date

28/11/1997

Volume

1362

Pages

29 - 38

Keywords

3T3 Cells, Androstadienes, Androstenes, Animals, Bombesin, Cell Division, Enzyme Inhibitors, Insulin, Mice, Phosphatidylinositols, Phosphoinositide-3 Kinase Inhibitors, Phospholipases, Phospholipids, Phosphorylation, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tyrosine, Wortmannin