Tyrosine kinase inhibitor as a novel signal transduction and antiproliferative agent: prostate cancer.
In prostate cancer cells, the binding of peptide growth factors to specific receptors increases tyrosine kinases (TK) activity to regulate cell proliferation, cell differentiation, and signaling processes. To determine whether inhibition of receptor TK activity inhibits tumor growth, we studied the effects of a tyrosine kinase inhibitor, RG-13022 (tyrphostin), on cultured human prostate cancer cells. RG-13022 significantly inhibited TGF alpha-induced phosphorylation of EGF receptor (EGFR). This compound inhibited TGF alpha-stimulated [3H]thymidine incorporation in a dose-dependent manner with IC50 being 30 microM. Clonogenicity in soft agar was reduced in the presence of RG-13022. Inhibitory effects were also observed in androgen-positive LNCaP cells and androgen-negative PC3 cells. RG-13022 not only inhibited TGF alpha-induced growth but also growth stimulated by epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF) and serum. In addition, RG-13022 also blocked androgen-stimulated cell proliferation, suggesting that functioning TK pathways are required for androgen-induced growth. This novel synthetic inhibitor may be useful in providing a new strategy for future therapeutic intervention for prostate cancer.
Kondapaka
B S
BS
Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Reddy
K B
KB
D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects / Q000378:metabolism; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020032:Tyrphostins
D000728:Androgens; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C070274:RG 13022; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases