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.
authors.affiliation: From the Departments of Dermatology and.
authors.forename: Zhuzhen Z
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: From the Departments of Dermatology and.
authors.forename: Eunice E
authors.initials: EE
authors.lastname: Lee
authors.affiliation: the Children's Medical Center Research Institute, the University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: From the Departments of Dermatology and.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Pediatrics, the University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Zia
authors.affiliation: From the Departments of Dermatology and.|the Eugene McDermott Center for Human Growth and Development, the University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Donald
authors.initials: D
authors.lastname: Glass
authors.affiliation: the Children's Medical Center Research Institute, the University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.|Pediatrics, the University of Texas Southwestern Medical Center, Dallas, Texas 75390.|the Eugene McDermott Center for Human Growth and Development, the University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.affiliation: From the Departments of Dermatology and richard.wang@utsouthwestern.edu.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
mesh_terms: D001205:Ascorbic Acid / Q000009:adverse effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D003683:Dehydroascorbic Acid / Q000009:adverse effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010427:Pentose Phosphate Pathway
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D005947:Glucose; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid
keywords: cancer; erythrocyte; glucose metabolism; glucose-6-phosphate dehydrogenase (G6PD or G6PDH); glycolysis; hydrogen peroxide; metabolomics; oxidative stress; pentose phosphate pathway (PPP); vitamin C