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J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):33-9. doi: 10.1016/j.jsbmb.2008.12.016. Epub 2009 Jan 9.

Potential of l-buthionine sulfoximine to enhance the apoptotic action of estradiol to reverse acquired antihormonal resistance in metastatic breast cancer.

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  • 1Department of Medical Sciences, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, United States.

Abstract

L-Buthionine sulfoximine (BSO) is a potent inhibitor of glutathione biosynthesis and studies have shown that it is capable of enhancing the apoptotic effects of several chemotherapeutic agents. Previous studies have shown that long-term antihormonal therapy leads to acquired drug resistance and that estrogen, which is normally a survival signal, is a potent apoptotic agent in these resistant cells. Interestingly, we have developed an antihormone-resistant breast cancer cell line, MCF-7:2A, which is resistant to estrogen-induced apoptosis but has elevated levels of glutathione. In the present study, we examined whether BSO is capable of sensitizing antihormone-resistant MCF-7:2A cells to estrogen-induced apoptosis. Our results showed that treatment of MCF-7:2A cells with 1nM E2 plus 100muM BSO combination for 1 week reduced the growth of these cells by almost 80-90% whereas the individual treatments had no significant effect on growth. TUNEL and 4',6-diamidino-2-phenylindole (DAPI) staining showed that the inhibitory effect of the combination treatment was due to apoptosis. Our data indicates that glutathione participates in retarding apoptosis in antihormone-resistant human breast cancer cells and that depletion of this molecule by BSO may be critical in predisposing resistant cells to estrogen-induced apoptosis.

PMID:
19167492
PMCID:
PMC2869080
DOI:
10.1016/j.jsbmb.2008.12.016
[PubMed - indexed for MEDLINE]
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