Inhibition of phospholipid signalling and proliferation of Swiss 3T3 cells by the wortmannin analogue demethoxyviridin

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Abstract

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 μM and cytotoxic effects at 10 μM. 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.

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Cross, M. J., Hodgkin, M. N., Plumb, J. A., Brunton, V. G., Stewart, A., MacAully, G., … Wakelam, M. J. O. (1997). Inhibition of phospholipid signalling and proliferation of Swiss 3T3 cells by the wortmannin analogue demethoxyviridin. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1362(1), 29–38. https://doi.org/10.1016/S0925-4439(97)00053-7

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