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

  • Cross M
  • Hodgkin M
  • Plumb J
 et al. 
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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 A2in 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.

Author-supplied keywords

  • Cell- proliferation
  • Demethoxyviridin
  • Phospholipases
  • Signal-transduction
  • Wortmannin

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Authors

  • Michael J. Cross

  • Matthew N. Hodgkin

  • Jane A. Plumb

  • Allison Stewart

  • Graeme MacAully

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