Journal article
Inhibition of glutamate cysteine ligase activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose
Cancer research (Chicago, Ill.), Vol.66(3), pp.1605-1610
2006
DOI: 10.1158/0008-5472.CAN-05-3462
PMID: 16452219
Abstract
It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-D-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-D-glucose, and total glutathione content as well as the expression of the first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)] were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-D-glucose exposure using l-buthionine-[S,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-D-glucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steady-state levels of pro-oxidants as assayed using an oxidation-sensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-d-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-D-glucose-mediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-D-glucose-induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress.
Details
- Title: Subtitle
- Inhibition of glutamate cysteine ligase activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose
- Creators
- Kelly K ANDRINGA - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesMitchell C COLEMAN - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesNukhet AYKIN-BURNS - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesMichael J HITCHLER - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesSusan A WALSH - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesFrederick E DOMANN - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United StatesDouglas R SPITZ - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.66(3), pp.1605-1610
- Publisher
- American Association for Cancer Research; Philadelphia, PA
- DOI
- 10.1158/0008-5472.CAN-05-3462
- PMID
- 16452219
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 2006
- Academic Unit
- Radiology; Pathology; Orthopedics and Rehabilitation; Surgery; Radiation Oncology
- Record Identifier
- 9984040020302771
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