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Differential induction of cell death in human glioma cell lines by sodium nitroprusside
Author(s) -
Blackburn Robert V.,
Galoforo Sandra S.,
Berns Christine M.,
Motwani Nalini M.,
Corry Peter M.,
Lee Yong J.
Publication year - 1998
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19980315)82:6<1137::aid-cncr19>3.0.co;2-7
Subject(s) - cytotoxicity , protein kinase c , transfection , cell culture , sodium nitroprusside , microbiology and biotechnology , cancer research , glioma , cytotoxic t cell , in vitro , biology , medicine , kinase , genetics , endocrinology , nitric oxide
BACKGROUND High grade gliomas represent very aggressive and lethal forms of human cancer, which often exhibit recurrence after surgical intervention and resistance to 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)α gene in mediating resistance to SNP‐induced killing in U343 cells was investigated using antisense oligonucleotide inhibition. Stable transfection and overexpression of the PKCα gene in the SNP‐susceptible cell line U251 was performed to further implicate PKCα 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 PKCα 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 PKCα antisense oligonucleotides into U343 cells. Conversely, enhanced PKC activity in PKCα‐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 PKC activity. bcl ‐2 levels in these cells can be altered through modulation of PKC signaling, specifically, by induction or inhibition of PKCα. These in vitro results provide an interesting basis for further study into the potential use of SNP for treatment of human gliomas in patients receiving combination therapy with conventional chemotherapeutic agents that exhibit PKC inhibitory activity. Cancer 1998;82:1137‐45. © 1998 American Cancer Society.