Induction of apoptosis and inhibition of small cell lung cancer growth by the quinoxaline tyrphostins.
Coexpression of the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF), occurs in a high proportion of small cell lung cancers (SCLCs) and drives an autocrine loop that enhances proliferation. To determine whether this autocrine loop affects apoptosis, SCLC cells expressing only SCF or both SCF and Kit were deprived of growth factors for 72 h and the relative number of cells undergoing apoptosis was assessed using nuclear DNA content and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays. Coexpression of SCF and Kit inhibited apoptosis; apoptosis could, in turn, be enhanced by the addition of the quinoxaline tyrosine kinase inhibitors, which are specific antagonists of the platelet-derived growth factor receptor and Kit. Treatment of the H526 cell line, which is growth-stimulated by soluble SCF, with AG1296 resulted in a marked decrease in growth and an increase in apoptosis in a dose-dependent fashion. Growth inhibition correlated well with the inhibition of Kit tyrosine phosphorylation. The AG1296 compound at its maximum soluble concentration inhibited the growth of 5 of 6 SCLC cell lines in complete medium by an average of 50%. These data suggest that optimized pharmacological inhibitors of Kit activity may be a new class of compounds potentially useful in the treatment of SCLC.
Krystal
G W
GW
Department of Medicine, Medical College of Virginia/Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, 23249, USA.
Carlson
P
P
Litz
J
J
D017209:Apoptosis / Q000187:drug effects*; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020032:Tyrphostins
D004791:Enzyme Inhibitors; D009570:Nitriles; D011810:Quinoxalines; D019089:Stem Cell Factor; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D011505:Protein-Tyrosine Kinases