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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nat+Med
2017 ; 23
(1
): 120-127
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Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen
species and suppresses tumor growth
#MMPMID27869804
Cramer SL
; Saha A
; Liu J
; Tadi S
; Tiziani S
; Yan W
; Triplett K
; Lamb C
; Alters SE
; Rowlinson S
; Zhang YJ
; Keating MJ
; Huang P
; DiGiovanni J
; Georgiou G
; Stone E
Nat Med
2017[Jan]; 23
(1
): 120-127
PMID27869804
show ga
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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