Buthionine sulfoximine sensitizes antihormone-resistant human breast cancer cells to estrogen-induced apoptosisReportar como inadecuado




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Breast Cancer Research

, 10:R104

First Online: 05 December 2008Received: 04 September 2008Revised: 11 November 2008Accepted: 05 December 2008

Abstract

IntroductionEstrogen deprivation using aromatase inhibitors is one of the standard treatments for postmenopausal women with estrogen receptor ER-positive breast cancer. However, one of the consequences of prolonged estrogen suppression is acquired drug resistance. Our group is interested in studying antihormone resistance and has previously reported the development of an estrogen deprived human breast cancer cell line, MCF-7:5C, which undergoes apoptosis in the presence of estradiol. In contrast, another estrogen deprived cell line, MCF-7:2A, appears to have elevated levels of glutathione GSH and is resistant to estradiol-induced apoptosis. In the present study, we evaluated whether buthionine sulfoximine BSO, a potent inhibitor of glutathione GSH synthesis, is capable of sensitizing antihormone resistant MCF-7:2A cells to estradiol-induced apoptosis.

MethodsEstrogen deprived MCF-7:2A cells were treated with 1 nM 17β-estradiol E2, 100 μM BSO, or 1 nM E2 + 100 μM BSO combination in vitro, and the effects of these agents on cell growth and apoptosis were evaluated by DNA quantitation assay and annexin V and terminal deoxynucleotidyl transferase dUTP nick end-labeling TUNEL staining. The in vitro results of the MCF-7:2A cell line were further confirmed in vivo in a mouse xenograft model.

ResultsExposure of MCF-7:2A cells to 1 nM E2 plus 100 μM BSO combination for 48 to 96 h produced a sevenfold increase in apoptosis whereas the individual treatments had no significant effect on growth. Induction of apoptosis by the combination treatment of E2 plus BSO was evidenced by changes in Bcl-2 and Bax expression. The combination treatment also markedly increased phosphorylated c-Jun N-terminal kinase JNK levels in MCF-7:2A cells and blockade of the JNK pathway attenuated the apoptotic effect of E2 plus BSO. Our in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of BSO either as a single agent or in combination with E2 significantly reduced tumor growth of MCF-7:2A cells.

ConclusionsOur data indicates that GSH 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 E2-induced apoptotic cell death. We suggest that these data may form the basis of improving therapeutic strategies for the treatment of antihormone resistant ER-positive breast cancer.

AbbreviationsBSOL-buthionine sulfoximine

E217β-estradiol

ERestrogen receptor

FBSfetal bovine serum

GCSglutamylcysteine

GPx2glutathione peroxidase

GSglutathione synthetase

GSHglutathione

HandEhematoxylin and eosin

JNKc-Jun N-terminal kinase

Rh123rhodamine 123

SFSdextran coated charcoal-treated FBS

TUNELterminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr2208 contains supplementary material, which is available to authorized users.

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Autor: Joan S Lewis-Wambi - Helen R Kim - Chris Wambi - Roshani Patel - Jennifer R Pyle - Andres J Klein-Szanto - V Craig Jor

Fuente: https://link.springer.com/



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