Differential induction of cell death in human glioma cell lines by sodium nitroprusside
CANCER(1998)
Abstract
BACKGROUND, High grade gliomas represent very aggressive and lethal forms of human cancer, which often exhibit recurrence after surgical intervention and resistance tr conventional chemotherapeutic and radiologic treatment. The clinically approved antihypertensive agent sodium nitroprusside (SNP) has been shown to induce cytotoxicity toward a number of carcinoma cell lines in vitro. METHODS, Three human glioma cell lines were examined for susceptibility to the cytotoxic effects of SNP. The role of the protein kinase C (PKC)alpha gene in mediating resistance to SNP-induced killing in U343 cells was investigated using antisense oligonucleotide inhibition. Stable transfection and overexpression of the PKC alpha gene in the SNP-susceptible cell line U251 was performed to further implicate PKC alpha as a mediating factor in SNP cytotoxicity. In addition, the presence of bcl-2 protein in these cells was examined for possible correlation(s) with resistance to SNP. RESULTS, Exposure of U251 cells and LN-Z308 cells to 0.5 mM SNP resulted in significant cytotoxicity over a 72-hour period. U343 cells were resistant to SNP killing. U343 cells were shown to exhibit higher basal levels of PKC alpha and bcl-2 than either U251 or LN-Z308 cells. bcl-2 expression and resistance to SNP toxicity both were decreased by the introduction of PKC alpha antisense oligonucleotides into U343 cells. Conversely, enhanced PKC activity in PKC alpha-transfected U251 clones was associated with increased bcl-2 expression and greater resistance to SNP-induced toxicity relative to control transfected cells. CONCLUSIONS, SNP can induce cytotoxicity in glioma cells. The susceptibility of these glioma cells to nitroprusside-induced killing appears to be correlated inversely with bcl-2 and PE;C activity. bcl-2 levels in these cells can be altered through modulation of PKC signaling, specifically, by induction or inhibition of PKC alpha. These in vitro results provide an interesting basis for further study into the potential use of SNP for treatment elf human gliomas in patients receiving combination therapy wish conventional chemotherapeutic agents that exhibit PKC inhibitory activity. (C) 1998 American Cancer Society.
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Key words
glioma,nitroprusside,toxicity,protein kinase C-alpha,bcl-2
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