High levels of intracellular glutathione (GSH) are associated with resistence to anticancer therapies and chemoresistant phenotypes (1). For this reason, GSH depletion might represent a strategy to sensitize tumor cells to anticancer therapy. Buthionine sulfoximine (BSO) is a selective and irreversible inhibitor of -glutamylcysteine synthetase (-GCS), the rate-limiting enzyme in GSH biosynthesis; then, BSO has the capacity to drastically reduce GSH content. It has been reported that the depletion of GSH is often associated with cell death and onset of apoptosis (2-5). In the present study the comparative response of three different prostate cell lines to BSO-induced GSH depletion was analyzed. Experiments were performed on LNCaP and DU145, two different human prostatic cell lines which represent two different stages of the disease, and on BPH-1, non malignant cell line. Experimental parameters assessed were: GSH content, cell count, western blot analysis for heme oxygenase-1 and -GCS expression. Results obtained demonstrate that HO-1 and -GCS are differently expressed in the three cell lines and that effects evoked by BSO treatment depend on the cell type, the most relevant of which is the selective antiproliferative effect, observed only in DU145 cells. Diethyl maleate (DEM), an electrophilic agent which complexes GSH, is also able to induce apoptosis by activation of caspase downstream (2), however one of limitations associated with its use is the inability of DEM to selectively target tumor cells while sparing normal ones. Unlike DEM, BSO treatment seems to exert more targeted effcts which may be usefull in the therapy of prostate cancer.

Antiproliferative effect of glutathione depletion in normal and malignant prostate cell lines

DI GIACOMO, Claudia;SORRENTI, Valeria;CARDILE, Venera;ACQUAVIVA, ROSARIA
2012

Abstract

High levels of intracellular glutathione (GSH) are associated with resistence to anticancer therapies and chemoresistant phenotypes (1). For this reason, GSH depletion might represent a strategy to sensitize tumor cells to anticancer therapy. Buthionine sulfoximine (BSO) is a selective and irreversible inhibitor of -glutamylcysteine synthetase (-GCS), the rate-limiting enzyme in GSH biosynthesis; then, BSO has the capacity to drastically reduce GSH content. It has been reported that the depletion of GSH is often associated with cell death and onset of apoptosis (2-5). In the present study the comparative response of three different prostate cell lines to BSO-induced GSH depletion was analyzed. Experiments were performed on LNCaP and DU145, two different human prostatic cell lines which represent two different stages of the disease, and on BPH-1, non malignant cell line. Experimental parameters assessed were: GSH content, cell count, western blot analysis for heme oxygenase-1 and -GCS expression. Results obtained demonstrate that HO-1 and -GCS are differently expressed in the three cell lines and that effects evoked by BSO treatment depend on the cell type, the most relevant of which is the selective antiproliferative effect, observed only in DU145 cells. Diethyl maleate (DEM), an electrophilic agent which complexes GSH, is also able to induce apoptosis by activation of caspase downstream (2), however one of limitations associated with its use is the inability of DEM to selectively target tumor cells while sparing normal ones. Unlike DEM, BSO treatment seems to exert more targeted effcts which may be usefull in the therapy of prostate cancer.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/110198
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