K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction.
Growth factors are known to regulate glioma proliferation. The glioma cell lines U87 and T98G were examined for evidence of an autocrine stimulatory loop involving the neurotrophin family of growth factors. Although neurotrophin-3 and TrkC RNA were detected by reverse transcription-PCR, there was no evidence of significant interaction between neurotrophin-3 and its cognate receptor TrkC. The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and neuroblastoma cell proliferation. K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 microM, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evidence to support the existence of a neurotrophin-mediated autocrine loop. K252a, through inhibition of PDGF signal transduction, may be a novel therapeutic agent in the treatment of human gliomas.
Chin
L S
LS
Department of Neurosurgery, Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. lchin@surgery1.ab.umd.edu
Murray
S F
SF
Zitnay
K M
KM
Rami
B
B
D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002227:Carbazoles / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000633:toxicity*; D066246:ErbB Receptors / Q000032:analysis; D005910:Glioma; D006801:Humans; D026121:Indole Alkaloids; D009414:Nerve Growth Factors / Q000235:genetics; D020933:Neurotrophin 3; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000032:analysis; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D017931:DNA Primers; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D010982:Platelet-Derived Growth Factor; C049985:staurosporine aglycone; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D011493:Protein Kinase C