Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer.

Abstract

Inhibition of glycolysis using 2-deoxy-d-glucose (2DG, 20mM, 24-48h) combined with inhibition of the pentose cycle using dehydroepiandrosterone (DHEA, 300µM, 24-48h) increased clonogenic cell killing in both human prostate (PC-3 and DU145) and human breast (MDA-MB231) cancer cells via a mechanism involving thiol-mediated oxidative stress. Surprisingly, when 2DG+DHEA treatment was combined with an inhibitor of glutathione (GSH) synthesis (l-buthionine sulfoximine; BSO, 1mM) that depleted GSH>90% of control, no further increase in cell killing was observed during 48h exposures. In contrast, when an inhibitor of thioredoxin reductase (TrxR) activity (Auranofin; Au, 1µM), was combined with 2DG+DHEA or DHEA-alone for 24h, clonogenic cell killing was significantly increased in all three human cancer cell lines. Furthermore, enhanced clonogenic cell killing seen with the combination of DHEA+Au was nearly completely inhibited using the thiol antioxidant, N-acetylcysteine (NAC, 20mM). Redox Western blot analysis of PC-3 cells also supported the conclusion that thioredoxin-1 (Trx-1) oxidation was enhanced by treatment DHEA+Au and inhibited by NAC. Importantly, normal human mammary epithelial cells (HMEC) were not as sensitive to 2DG, DHEA, and Au combinations as their cancer cell counterparts (MDA-MB-231). Overall, these results support the hypothesis that inhibition of glycolysis and pentose cycle activity, combined with inhibition of Trx metabolism, may provide a promising strategy for selectively sensitizing human cancer cells to oxidative stress-induced cell killing.

• Authors: Ling Li, Melissa A Fath, Peter M Scarbrough, Walter H Watson, Douglas R Spitz
• Journal: Redox biology (Redox Biol) Vol. 4 Pg. 127-35 ( 2015) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 25560241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• TXN protein, human
• Dehydroepiandrosterone
• Thioredoxins
• Deoxyglucose

Topics

• Antioxidants (administration & dosage)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Dehydroepiandrosterone (administration & dosage)
• Deoxyglucose (administration & dosage)
• Drug Synergism
• Female
• Glycolysis (drug effects)
• Humans
• Male
• Oxidative Stress (drug effects)
• Pentose Phosphate Pathway (drug effects)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Thioredoxins (antagonists & inhibitors, metabolism)