PMID: 9533547May 14, 1998Paper

Chemosensitization of glioblastoma cells to bis-dichloroethyl-nitrosourea with tyrphostin AG17

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
B C Liang, E Ullyatt

Abstract

Recent data have suggested that mitochondria play a supportive role in maintaining the tumorigenic phenotype. Indeed, antimitochondrial agents have been hypothesized to be potential chemosensitizers to human malignancy. We assessed the utility of this approach by characterizing the antimitochondrial activity of 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile (AG17), in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in two human glioblastoma cell lines. AG17 (NSC 242557) is a tyrphostin that has been thought to have some antimitochondrial activity, with limited tyrosine kinase antagonism, and was used at noncytotoxic and nongrowth-inhibitory concentrations (0.25 microM). Glioblastoma cells were incubated in AG17, and changes in mitochondrial activity were determined. Tumor cells became auxotrophically dependent on uridine and pyruvate, indicating the lack of a functioning respiratory chain. Despite this, cells continued to exhibit no growth-inhibitory effects. Exposure to AG17 was associated with significant depolarization of the mitochondrial membrane potential and decreases in mitochondrial mass in both glioblastoma cell lines, correlating with the finding of auxotrophic dependence. In contrast, normal human...Continue Reading

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