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Nat Med. 2017 Jan;23(1):120-127. doi: 10.1038/nm.4232. Epub 2016 Nov 21.

Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

Author information

1
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
2
Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA.
3
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA.
5
Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
6
Aeglea Biotherapeutics, Austin, Texas, USA.
7
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53-/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.

PMID:
27869804
PMCID:
PMC5218918
DOI:
10.1038/nm.4232
[Indexed for MEDLINE]
Free PMC Article

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