Effect of tyrphostin combined with a substance P related antagonist on small cell lung cancer cell growth in vitro.
The protein tyrosine kinase inhibitor [(3,4,5,-trihydroxyphenyl)-methylene]-propanedinitrile (tyrphostin) was originally designed to inhibit polypeptide growth factor receptor signalling, but was also found to inhibit neuropeptide stimulated tyrosine phosphorylation and mitogenesis in Swiss 3T3 cells [J Biol Chem 1993, 268, 9548-9554]. Here, we demonstrate that tyrphostin inhibits in vitro colony growth of the H-345 and H-69 small cell lung cancer (SCLC) cell lines stimulated by the neuropeptides, bombesin and bradykinin, respectively. This effect was dose-dependent and, at tyrphostin concentrations above 5 microM, both background and neuropeptide stimulated colony formation were reduced. In liquid culture, tyrphostin inhibited the growth of the H-345 and H-69 SCLC cell lines with an IC50 of 7 microM. Time course experiments in liquid culture revealed that tyrphostin delayed the rate of entry of both SCLC cell lines into rapid phase growth and reduced the number of cells reaching a plateau phase of growth compared with control cells. Furthermore, tyrphostin concentrations at or above 50 microM reduced the number of cells present over time compared with untreated cells. When combined with a substance P (SP) analogue, which inhibits the action of multiple neuropeptides and SCLC cell growth, both in semisolid media and liquid culture, tyrphostin additively inhibited the growth of the H-345 and H-69 SCLC cell lines in liquid culture.
Seckl
M J
MJ
Imperial Cancer Research Fund, London, U.K.
Rozengurt
E
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins
D000970:Antineoplastic Agents; D009570:Nitriles; D010446:Peptide Fragments; D020032:Tyrphostins; C079836:tyrphostin 25; C046958:substance P (6-11), Arg(6)-Trp(7,9)-Me-Phe(8)-; D013373:Substance P; D011505:Protein-Tyrosine Kinases