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

Ling Li; Melissa A Fath; Peter M Scarbrough; Walter H Watson; Douglas R Spitz

doi:10.1016/j.redox.2014.12.001

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

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

Ling Li, Melissa A Fath, Peter M Scarbrough, Walter H Watson and Douglas R Spitz

Redox biology, Vol.4(C), pp.127-135

2015

DOI: 10.1016/j.redox.2014.12.001

PMCID: PMC4309850

PMID: 25560241

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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.

Pentose Phosphate Pathway - drug effects

Prostatic Neoplasms - metabolism

Prostatic Neoplasms - pathology

Humans

Dehydroepiandrosterone - administration & dosage

Male

Breast Neoplasms - drug therapy

Glycolysis - drug effects

Breast Neoplasms - metabolism

Drug Synergism

Breast Neoplasms - pathology

Antioxidants - administration & dosage

Cell Line, Tumor

Deoxyglucose - administration & dosage

Female

Thioredoxins - metabolism

Thioredoxins - antagonists & inhibitors

Oxidative Stress - drug effects

Prostatic Neoplasms - drug therapy

Details

Title: Subtitle: Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer
Creators: Ling Li - Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
Melissa A Fath - Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
Peter M Scarbrough - Duke Cancer Institute, Duke University, Durham, NC 27705, USA
Walter H Watson - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40292, USA
Douglas R Spitz - Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: douglas-spitz@uiowa.edu
Resource Type: Journal article
Publication Details: Redox biology, Vol.4(C), pp.127-135
DOI: 10.1016/j.redox.2014.12.001
PMID: 25560241
PMCID: PMC4309850
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Netherlands
Grant note: P30 ES005605 / NIEHS NIH HHS T32 CA078586 / NCI NIH HHS R01CA100045 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R01CA133114 / NCI NIH HHS R01 CA133114 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01CA182804 / NCI NIH HHS T32CA078586 / NCI NIH HHS P30CA086862 / NCI NIH HHS R21 CA139182 / NCI NIH HHS R01 CA100045 / NCI NIH HHS R21CA139182 / NCI NIH HHS
Language: English
Date published: 2015
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984047740402771

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