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Cited by 538

The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.

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

Open access
Cramer, Shira L, Saha, Achinto, Liu, Jinyun, Tadi, Surendar, Tiziani, Stefano, Yan, Wupeng, Triplett, Kendra, Lamb, Candice, Alters, Susan E, Rowlinson, Scott, Zhang, Yan Jessie, Keating, Michael J, Huang, Peng, DiGiovanni, John, Georgiou, George, Stone, Everett·2017·Nature Medicine
DOI 10.1038/nm.4232
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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.

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Metadata

Authors
Cramer, S. L., Saha, A., Liu, J., Tadi, S., Tiziani, S., Yan, W., Triplett, K., Lamb, C., Alters, S. E., Rowlinson, S., Zhang, Y. J., Keating, M. J., Huang, P., DiGiovanni, J., Georgiou, G., & Stone, E.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-11-21
Volume
23
Issue
1
Pages
120-127
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4232
OpenAlex
W2554956457
Cited by
538
References
57
FWCI
15.05
Type
journal article
Language
en
Open access
green

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