Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo.
OBJECTIVE
Recently we demonstrated that phosphatidylinositol 3-kinase (PI3K) is overexpressed in human lung cancer. This study evaluated whether the PI3K inhibiting agent wortmannin affects proliferation of human lung cancer cells in vitro and in vivo.


METHODS
Effects of exposure of human non-small-cell lung cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in vitro by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we examined the effects of blocking PI3K by wortmannin prior to xenotransplantation of human NSCLC cells into SCID-bg mice and the effect of systemic wortmannin administration following intrapulmonary xenotransplantation of human NSCLC.


RESULTS
Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin inhibited proliferation in correlation to concentration in vitro. In vivo the blocking of PI3K by wortmannin prior to xenotransplantation caused a significant delay in the growth of subcutaneously induced tumors. Systemic wortmannin administration increased mean survival after intrapulmonary xenotransplantation of human NSCLC significantly by 38% and 47%.


CONCLUSIONS
These data suggest inhibition of PI3K activity as a potential target for treatment of human NSCLC. Systemic toxicity of wortmannin requires development of improved PI3K inhibitors with favorable pharmacological properties.
Boehle
Arnd Steffen
AS
Department for General Surgery and Thoracic Surgery, Christian Albrecht University, Arnold-Heller-Strasse 7, 24105 Kiel, Germany. boehle@surgery.uni-kiel.de
Kurdow
Roland
R
Boenicke
Lars
L
Schniewind
Bodo
B
Faendrich
Fred
F
Dohrmann
Peter
P
Kalthoff
Holger
H
D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000503:physiopathology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D016513:Mice, SCID; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011897:Random Allocation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D004273:DNA, Neoplasm; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin