title: Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.
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.
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Shira L
authors.initials: SL
authors.lastname: Cramer
authors.affiliation: Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Achinto
authors.initials: A
authors.lastname: Saha
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Surendar
authors.initials: S
authors.lastname: Tadi
authors.affiliation: Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tiziani
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Wupeng
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Triplett
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Lamb
authors.affiliation: Aeglea Biotherapeutics, Austin, Texas, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Alters
authors.affiliation: Aeglea Biotherapeutics, Austin, Texas, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rowlinson
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Yan Jessie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Everett
authors.initials: E
authors.lastname: Stone
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003542:Cystathionine gamma-Lyase / Q000494:pharmacology*; D003545:Cysteine / Q000187:drug effects* / Q000378:metabolism; D003553:Cystine / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011092:Polyethylene Glycols; D003553:Cystine; D003542:Cystathionine gamma-Lyase; C000621859:cyst(e)inase protein, human; D005978:Glutathione; D003545:Cysteine