Abstract
The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies. Cancer cells are protected from VC-mediated cell death when co-cultured with physiologically relevant numbers of erythrocytes. Pharmacological doses of VC induce oxidative stress, GSH depletion, and increased glucose flux through the oxidative pentose phosphate pathway (PPP) in erythrocytes. Incubation of erythrocytes with VC induced hemolysis, which was exacerbated in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD) patients and rescued by antioxidants. Thus, erythrocytes protect cancer cells from VC-induced oxidative stress and undergo hemolysis in vitro, despite activation of the PPP. These results have implications on the use of high dose VC in ongoing clinical trials and highlight the importance of the PPP in the response to oxidative stress.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 22861-22867 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 291 |
| Issue number | 44 |
| DOIs | |
| State | Published - Oct 28 2016 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress. / Zhang, Zhuzhen Z.; Lee, Eunice E.; Sudderth, Jessica; Yue, Yangbo; Zia, Ayesha; Glass, Donald; Deberardinis, Ralph J.; Wang, Richard C.
In: Journal of Biological Chemistry, Vol. 291, No. 44, 28.10.2016, p. 22861-22867.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress
AU - Zhang, Zhuzhen Z.
AU - Lee, Eunice E.
AU - Sudderth, Jessica
AU - Yue, Yangbo
AU - Zia, Ayesha
AU - Glass, Donald
AU - Deberardinis, Ralph J.
AU - Wang, Richard C.
PY - 2016/10/28
Y1 - 2016/10/28
N2 - The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies. Cancer cells are protected from VC-mediated cell death when co-cultured with physiologically relevant numbers of erythrocytes. Pharmacological doses of VC induce oxidative stress, GSH depletion, and increased glucose flux through the oxidative pentose phosphate pathway (PPP) in erythrocytes. Incubation of erythrocytes with VC induced hemolysis, which was exacerbated in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD) patients and rescued by antioxidants. Thus, erythrocytes protect cancer cells from VC-induced oxidative stress and undergo hemolysis in vitro, despite activation of the PPP. These results have implications on the use of high dose VC in ongoing clinical trials and highlight the importance of the PPP in the response to oxidative stress.
AB - The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies. Cancer cells are protected from VC-mediated cell death when co-cultured with physiologically relevant numbers of erythrocytes. Pharmacological doses of VC induce oxidative stress, GSH depletion, and increased glucose flux through the oxidative pentose phosphate pathway (PPP) in erythrocytes. Incubation of erythrocytes with VC induced hemolysis, which was exacerbated in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD) patients and rescued by antioxidants. Thus, erythrocytes protect cancer cells from VC-induced oxidative stress and undergo hemolysis in vitro, despite activation of the PPP. These results have implications on the use of high dose VC in ongoing clinical trials and highlight the importance of the PPP in the response to oxidative stress.
UR - http://www.scopus.com/inward/record.url?scp=84993995266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84993995266&partnerID=8YFLogxK
U2 - 10.1074/jbc.C116.748848
DO - 10.1074/jbc.C116.748848
M3 - Article
C2 - 27660392
AN - SCOPUS:84993995266
VL - 291
SP - 22861
EP - 22867
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 44
ER -