© 2000 by Society
© 2000 by the Society forNeuro-Oncology
Inhibition of cell growth in human glioblastoma cell lines byfarnesyltransferase inhibitor SCH66336
The University of Texas M.D. Anderson Cancer Center, Department ofNeuro-Oncology, Houston, TX 77030
2 Address correspondence and reprint requests to W.K. Alfred Yung Chairman AdInterim, Department of Neuro-Oncology, Box 100, The University of Texas M.D.Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030.
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Abstract |
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Ras activation occurs through stimulation of an upstream growth factorreceptor such as epidermal growth factor receptor (EGFR). The ultimate effectof Ras is to induce nuclear transcription via a signaling pathway sequentiallyinvolving Raf, MAP kinase kinase (MEK), and mitogen-activated protein kinase(MAPK). To transform cells, Ras oncoproteins must be posttranslationallymodified with a farnesyl group in a reaction catalyzed by farnesyl proteintransferase. Farnesyltransferase inhibitors, therefore, have been proposed aspotent anticancer agents. This study demonstrates the growth-inhibitoryeffects of farnesyltransferase inhibitor SCH66336 on human glioblastoma celllines U-251 MG, U-251/E4 MG (a stably transfected cell line with elevated EGFRexpression), and U-87 MG. As determined by(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) and viability assays, the concentration required toachieve 50% inhibition (IC50) ranged from 30 µM (single 24-htreatment) to 10 µM (5-day treatment). U-251/E4 MG with overexpression ofEGFR were more sensitive than U-251 MG parental cells. These observations werealso supported by soft agar analysis. Cells treated with SCH66336 underwent G2arrest. Western blot analysis revealed a decrease in phospho-MAPK levels upontreatment with 10 µM SCH66336, whereas MAPK levels were unaffected by thedrug. Interestingly, increased expression of EGFR was observed in U-251 MG andU-251/E4 MG but not in U-87 MG in the presence of the inhibitor. These resultsdemonstrate that SCH66336 inhibits viability and anchorage-independent growthin a time- and dose-dependent manner in glioblastoma cell lines U-251 MG,U-251/E4 MG, and U-87 MG via a signal transduction pathway involving thedown-regulation of phospho-MAPK. Overexpression of EGFR appears to altercellular sensitivity to farnesyltransferase inhibitors. This may have aparticularly important implication in glioblastoma, where over 50% of tumorshave amplification and overexpression of EGFR.
Received March 16, 2000; Accepted April 10, 2000
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