Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress

Zhuzhen Z. Zhang, Eunice E. Lee, Jessica Sudderth, Yangbo Yue, Ayesha Zia, Donald Glass, Ralph J. Deberardinis, Richard C. Wang

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)22861-22867
Number of pages7
JournalJournal of Biological Chemistry
Volume291
Issue number44
DOIs
StatePublished - Oct 28 2016

Fingerprint

Pentoses
Pentose Phosphate Pathway
Oxidative stress
Hemolysis
Ascorbic Acid
Glutathione
Oxidative Stress
Erythrocytes
Chemical activation
Phosphates
Cells
Neoplasms
Cell death
Cell Death
Clinical Trials
Erythrocyte Count
Glucosephosphate Dehydrogenase
Biological Availability
Antioxidants

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 journalArticle

@article{1d89afbfa5e0491e9e464c352f4efe7b,
title = "Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress",
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.",
author = "Zhang, {Zhuzhen Z.} and Lee, {Eunice E.} and Jessica Sudderth and Yangbo Yue and Ayesha Zia and Donald Glass and Deberardinis, {Ralph J.} and Wang, {Richard C.}",
year = "2016",
month = "10",
day = "28",
doi = "10.1074/jbc.C116.748848",
language = "English (US)",
volume = "291",
pages = "22861--22867",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "44",

}

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 -