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Dexamethasone pre-treatment interferes with apoptotic death in glioma cells
A M Gorman1, U A Hirt, S Orrenius
1Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institute, Box 210, S-171 77, Stockholm, Sweden.
Abstract:
Glucocorticoids are known to influence the ability of cells to undergo apoptosis, directly inducing apoptosis in thymocytes while inhibiting it in hepatoma and carcinoma cells. Dexamethasone, a synthetic glucocorticoid, is reported to induce partial resistance to certain anticancer drugs in glioma cell lines. In the present study, the effect of dexamethasone on apoptosis of glioma and astrocytoma cell lines was investigated. Exposure of D384 human astrocytoma and C6 rat glioma cells to staurosporine induced apoptosis as judged by the formation of condensed nuclei and caspase activation. Pre-treatment of cells with dexamethasone caused a reduction in staurosporine-induced apoptosis. In addition, dexamethasone also conferred protection against the induction of apoptosis by anticancer agents including camptothecin and etoposide. The protective effect of dexamethasone was dose and time dependent, with maximal protection obtained with concentrations equal to or greater than 100 nM and a pre-incubation period of at least 24h. The earliest significant inhibition was seen with a pre-incubation period of 8h. Co-treatment with the glucocorticoid receptor antagonist RU38486 abolished the effect of dexamethasone, indicating that the protection due to dexamethasone is mediated via this receptor. Dexamethasone was found to induce a time-dependent up-regulation of Bcl-x(L) protein expression. However, the ability of cytochrome c/dATP to activate the caspase cascade in cytosolic extracts of D384 cells was unaffected by prior exposure of the cells to dexamethasone (1 microM) for 48 h. In conclusion, dexamethasone inhibits the induction of apoptosis in astrocytoma cells, probably via an up-regulation of Bcl-x(L), which could prevent cytochrome c release from mitochondria and subsequent caspase activation. Since glucocorticoids are often used in the treatment of gliomas to relieve cerebral oedema, the inhibition of apoptosis by these compounds could potentially interfere with the efficacy of chemotherapeutic drugs.
Insights
Dexamethasone inhibits apoptosis in glioma and astrocytoma cells, potentially reducing chemotherapy effectiveness. This glucocorticoid effect is mediated by the glucocorticoid receptor and Bcl-x(L) up-regulation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Glucocorticoids modulate apoptosis differently across cell types.
- Dexamethasone, a synthetic glucocorticoid, has shown potential to induce resistance to anticancer drugs in glioma cell lines.
Purpose of the Study:
- To investigate the effect of dexamethasone on apoptosis in glioma and astrocytoma cell lines.
- To determine the mechanism and clinical implications of dexamethasone's influence on apoptosis in these cancer cells.
Main Methods:
- Human astrocytoma (D384) and rat glioma (C6) cells were exposed to staurosporine, camptothecin, or etoposide to induce apoptosis.
- Cells were pre-treated with dexamethasone and/or the glucocorticoid receptor antagonist RU38486.
- Apoptosis was assessed by nuclear condensation and caspase activation.
- Bcl-x(L) protein expression and caspase cascade activation in cytosolic extracts were analyzed.
Main Results:
- Dexamethasone pre-treatment significantly reduced staurosporine-, camptothecin-, and etoposide-induced apoptosis in a dose- and time-dependent manner.
- The protective effect was mediated through the glucocorticoid receptor, as confirmed by RU38486 antagonism.
- Dexamethasone up-regulated Bcl-x(L) protein expression but did not affect cytochrome c/dATP-mediated caspase activation in cytosolic extracts.
Conclusions:
- Dexamethasone inhibits apoptosis induction in astrocytoma and glioma cells, likely through Bcl-x(L) up-regulation, preventing mitochondrial cytochrome c release and subsequent caspase activation.
- Given the common use of glucocorticoids in glioma treatment for cerebral edema, this anti-apoptotic effect may compromise chemotherapy efficacy.