Le. Lemke et al., Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase, CANC CHEMOT, 44(6), 1999, pp. 491-497
Purpose: Phosphatidylinositol (PtdIns) 3-kinase is an important mediator of
many cellular functions. The study of PtdIns 3-kinase has been facilitated
by the existence of the potent irreversible inhibitor of p110 PtdIns 3-kin
ase, wortmannin. The purpose of the study was to investigate the relationsh
ip between the cell growth inhibitory activity and antitumor activity of wo
rtmannin and inhibition of PtdIns 3-kinase. Methods: PtdIns 3-kinase activi
ty was measured in cells and tumors and the effects of wortmannin investiga
ted. Results: Wortmannin inhibited the growth of murine C3H and human MCF-7
mammary tumors in vivo. However, the ability of wortmannin to inhibit C3H
tumor growth was not related to inhibition of tumor PtdIns 3-kinase activit
y. The existence of wortmannin-insensitive PtdIns 3-kinase activity was dem
onstrated in C3H and MCF-7 cell culture lysates and solid tumors, and norma
l mouse tissue homogenates. In addition to being resistant to inhibition by
wortmannin, MCF-7 cell lysate total PtdIns 3-kinase activity was also resi
stant to five additional known inhibitors of p110 PtdIns 3-kinase. Partial
purification of wortmannin-insensitive PtdIns 3-kinase from MCF-7 cell lysa
te showed the activity to be independent of the PtdIns 3-kinase p85 regulat
ory subunit. Conclusion: The results of the current study demonstrate that
wortmannin can inhibit the growth of murine and human mammary tumors despit
e the presence of novel wortmannin-insensitive PtdIns 3-kinases in these ti
ssues suggesting that some other target is responsible for wortmannin's ant
itumor activity.