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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1997-06, Vol.57 (11), p.2203-2208
Main Authors: KRYSTAL, G. W, CARLSON, P, LITZ, J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Carcinoma, Small Cell - metabolism
Carcinoma, Small Cell - pathology
Cell Division - drug effects
DNA Fragmentation
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
General aspects
Humans
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Medical sciences
Nitriles - pharmacology
Pharmacology. Drug treatments
Phosphorylation
Precipitin Tests
Protein-Tyrosine Kinases - metabolism
Quinoxalines - pharmacology
Stem Cell Factor - metabolism
Stem Cell Factor - pharmacology
Tumor Cells, Cultured
Tyrphostins
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Summary: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.
ISSN:0008-5472
1538-7445