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Clin Cancer Res. 2015 Jul 15;21(14):3263-73. doi: 10.1158/1078-0432.CCR-14-1200. Epub 2015 Mar 26.

Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate.

Author information

1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
4
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. saras@jhmi.edu.

Abstract

PURPOSE:

Glutamine addiction in c-MYC-overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved.

EXPERIMENTAL DESIGN:

A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress-mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model.

RESULTS:

We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress-mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc-overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy.

CONCLUSIONS:

AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC-overexpressing breast cancers.

PMID:
25813021
PMCID:
PMC4696069
DOI:
10.1158/1078-0432.CCR-14-1200
[Indexed for MEDLINE]
Free PMC Article

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