Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase.
OBJECTIVE
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-kinase, wortmannin. The purpose of the study was to investigate the relationship between the cell growth inhibitory activity and antitumor activity of wortmannin and inhibition of PtdIns 3-kinase.


METHODS
PtdIns 3-kinase activity was measured in cells and tumors and the effects of wortmannin investigated.


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 activity. The existence of wortmannin-insensitive PtdIns 3-kinase activity was demonstrated in C3H and MCF-7 cell culture lysates and solid tumors, and normal mouse tissue homogenates. In addition to being resistant to inhibition by wortmannin, MCF-7 cell lysate total PtdIns 3-kinase activity was also resistant to five additional known inhibitors of p110 PtdIns 3-kinase. Partial purification of wortmannin-insensitive PtdIns 3-kinase from MCF-7 cell lysate showed the activity to be independent of the PtdIns 3-kinase p85 regulatory subunit.


CONCLUSIONS
The results of the current study demonstrate that wortmannin can inhibit the growth of murine and human mammary tumors despite the presence of novel wortmannin-insensitive PtdIns 3-kinases in these tissues suggesting that some other target is responsible for wortmannin's antitumor activity.
Lemke
L E
LE
Arizona Cancer Center, University of Arizona, Tucson AZ 85724-5024, USA.
Paine-Murrieta
G D
GD
Taylor
C W
CW
Powis
G
G
D000730:Androstadienes / Q000633:toxicity*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin