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

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 elev... Full description

Journal Title: Nature medicine 2017, Vol.23 (1), p.120-127
Main Author: Cramer, Shira L
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/27869804
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title: Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth
format: Article
creator:
  • 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
subjects:
  • Animals
  • Antioxidants
  • Blotting, Western
  • Bone grafts
  • Breast cancer
  • Breast Neoplasms - metabolism
  • Cancer
  • Carcinogenesis
  • Cell cycle
  • Cell death
  • Cell Line, Tumor
  • Chronic lymphatic leukemia
  • Cystathionine gamma-Lyase - pharmacology
  • Cysteine
  • Cysteine - drug effects
  • Cysteine - metabolism
  • Cystine
  • Cystine - drug effects
  • Cystine - metabolism
  • Cysts
  • Depletion
  • Enzymes
  • Female
  • Genetic aspects
  • Glutathione
  • Glutathione - metabolism
  • Health aspects
  • Humans
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell - genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
  • Lymphatic leukemia
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Oxidative Stress
  • Oxygen
  • p53 Protein
  • Pharmacology
  • Polyethylene Glycols - pharmacology
  • Primates
  • Prostate
  • Prostate cancer
  • Prostate carcinoma
  • Prostatic Neoplasms - metabolism
  • Reactive oxygen species
  • Reactive Oxygen Species - metabolism
  • Risk factors
  • Survival
  • Toxicity
  • Transporter
  • Tumor Suppressor Protein p53 - genetics
  • Tumors
  • Xenografts
  • Xenotransplantation
ispartof: Nature medicine, 2017, Vol.23 (1), p.120-127
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleSystemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth
creatorCramer, 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
creatorcontribCramer, 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
descriptionCancer 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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languageeng
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subjectAnimals ; Antioxidants ; Blotting, Western ; Bone grafts ; Breast cancer ; Breast Neoplasms - metabolism ; Cancer ; Carcinogenesis ; Cell cycle ; Cell death ; Cell Line, Tumor ; Chronic lymphatic leukemia ; Cystathionine gamma-Lyase - pharmacology ; Cysteine ; Cysteine - drug effects ; Cysteine - metabolism ; Cystine ; Cystine - drug effects ; Cystine - metabolism ; Cysts ; Depletion ; Enzymes ; Female ; Genetic aspects ; Glutathione ; Glutathione - metabolism ; Health aspects ; Humans ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Lymphatic leukemia ; Macaca fascicularis ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Neoplasm Transplantation ; Oxidative Stress ; Oxygen ; p53 Protein ; Pharmacology ; Polyethylene Glycols - pharmacology ; Primates ; Prostate ; Prostate cancer ; Prostate carcinoma ; Prostatic Neoplasms - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Risk factors ; Survival ; Toxicity ; Transporter ; Tumor Suppressor Protein p53 - genetics ; Tumors ; Xenografts ; Xenotransplantation
ispartofNature medicine, 2017, Vol.23 (1), p.120-127
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1Saha, Achinto
2Liu, Jinyun
3Tadi, Surendar
4Tiziani, Stefano
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6Triplett, Kendra
7Lamb, Candice
8Alters, Susan E
9Rowlinson, Scott
10Zhang, Yan Jessie
11Keating, Michael J
12Huang, Peng
13DiGiovanni, John
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15Stone, Everett
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0Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth
1Nature medicine
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descriptionCancer 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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0Animals
1Antioxidants
2Blotting, Western
3Bone grafts
4Breast cancer
5Breast Neoplasms - metabolism
6Cancer
7Carcinogenesis
8Cell cycle
9Cell death
10Cell Line, Tumor
11Chronic lymphatic leukemia
12Cystathionine gamma-Lyase - pharmacology
13Cysteine
14Cysteine - drug effects
15Cysteine - metabolism
16Cystine
17Cystine - drug effects
18Cystine - metabolism
19Cysts
20Depletion
21Enzymes
22Female
23Genetic aspects
24Glutathione
25Glutathione - metabolism
26Health aspects
27Humans
28Leukemia
29Leukemia, Lymphocytic, Chronic, B-Cell - genetics
30Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
31Lymphatic leukemia
32Macaca fascicularis
33Male
34Mice
35Mice, Knockout
36Mice, Transgenic
37Neoplasm Transplantation
38Oxidative Stress
39Oxygen
40p53 Protein
41Pharmacology
42Polyethylene Glycols - pharmacology
43Primates
44Prostate
45Prostate cancer
46Prostate carcinoma
47Prostatic Neoplasms - metabolism
48Reactive oxygen species
49Reactive Oxygen Species - metabolism
50Risk factors
51Survival
52Toxicity
53Transporter
54Tumor Suppressor Protein p53 - genetics
55Tumors
56Xenografts
57Xenotransplantation
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8Alters, Susan E
9Rowlinson, Scott
10Zhang, Yan Jessie
11Keating, Michael J
12Huang, Peng
13DiGiovanni, John
14Georgiou, George
15Stone, Everett
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titleSystemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth
authorCramer, 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
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0Animals
1Antioxidants
2Blotting, Western
3Bone grafts
4Breast cancer
5Breast Neoplasms - metabolism
6Cancer
7Carcinogenesis
8Cell cycle
9Cell death
10Cell Line, Tumor
11Chronic lymphatic leukemia
12Cystathionine gamma-Lyase - pharmacology
13Cysteine
14Cysteine - drug effects
15Cysteine - metabolism
16Cystine
17Cystine - drug effects
18Cystine - metabolism
19Cysts
20Depletion
21Enzymes
22Female
23Genetic aspects
24Glutathione
25Glutathione - metabolism
26Health aspects
27Humans
28Leukemia
29Leukemia, Lymphocytic, Chronic, B-Cell - genetics
30Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
31Lymphatic leukemia
32Macaca fascicularis
33Male
34Mice
35Mice, Knockout
36Mice, Transgenic
37Neoplasm Transplantation
38Oxidative Stress
39Oxygen
40p53 Protein
41Pharmacology
42Polyethylene Glycols - pharmacology
43Primates
44Prostate
45Prostate cancer
46Prostate carcinoma
47Prostatic Neoplasms - metabolism
48Reactive oxygen species
49Reactive Oxygen Species - metabolism
50Risk factors
51Survival
52Toxicity
53Transporter
54Tumor Suppressor Protein p53 - genetics
55Tumors
56Xenografts
57Xenotransplantation
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1Saha, Achinto
2Liu, Jinyun
3Tadi, Surendar
4Tiziani, Stefano
5Yan, Wupeng
6Triplett, Kendra
7Lamb, Candice
8Alters, Susan E
9Rowlinson, Scott
10Zhang, Yan Jessie
11Keating, Michael J
12Huang, Peng
13DiGiovanni, John
14Georgiou, George
15Stone, Everett
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7Lamb, Candice
8Alters, Susan E
9Rowlinson, Scott
10Zhang, Yan Jessie
11Keating, Michael J
12Huang, Peng
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abstractCancer 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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pmid27869804
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