Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress

Tanja Hadzic; Nükhet Aykin-Burns; Yueming Zhu; Mitchell C Coleman; Katie Leick; Geraldine M Jacobson; Douglas R Spitz

doi:10.1016/j.freeradbiomed.2010.01.018

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Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress

Journal article

Peer reviewed

Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress

Tanja Hadzic, Nükhet Aykin-Burns, Yueming Zhu, Mitchell C Coleman, Katie Leick, Geraldine M Jacobson and Douglas R Spitz

Free radical biology & medicine, Vol.48(8), pp.1024-1033

04/15/2010

DOI: 10.1016/j.freeradbiomed.2010.01.018

PMCID: PMC2843822

PMID: 20083194

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Abstract

Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species (i.e., hydrogen peroxide, H(2)O(2)) that may be compensated for by increased glucose metabolism, but the therapeutic significance of these observations is unknown. In this study, inhibitors of glucose (i.e., 2-deoxy-d-glucose, 2DG) and hydroperoxide (i.e., l-buthionine-S,R-sulfoximine, BSO) metabolism were utilized in combination with a chemotherapeutic agent, paclitaxel (PTX), thought to induce oxidative stress, to treat breast cancer cells. 2DG + PTX was more toxic than either agent alone in T47D and MDA-MB231 human breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H(2)O(2), total glutathione, and glutathione disulfide, accompanied the enhanced toxicity of 2DG + PTX in cancer cells. Antioxidants, including N-acetylcysteine and polyethylene glycol-conjugated catalase and superoxide dismutase, inhibited the toxicity of 2DG + PTX and suppressed parameters indicative of oxidative stress in cancer cells, whereas inhibition of glutathione synthesis using BSO further sensitized breast cancer cells to 2DG + PTX. These results show that combining inhibitors of glucose (2DG) and hydroperoxide (BSO) metabolism with PTX selectively (relative to normal cells) enhances breast cancer cell killing via H(2)O(2)-induced metabolic oxidative stress, and suggest that this biochemical rationale may be effectively utilized to treat breast cancers.

Buthionine Sulfoximine - pharmacology

Cell Survival - drug effects

Paclitaxel - pharmacology

Reactive Oxygen Species - metabolism

Humans

Breast Neoplasms - drug therapy

Glucose - antagonists & inhibitors

Hydrogen Peroxide - metabolism

Drug Synergism

Deoxyglucose - pharmacology

Fibroblasts - drug effects

Female

Oxidative Stress - drug effects

Tumor Cells, Cultured

Hydrogen Peroxide - antagonists & inhibitors

Details

Title: Subtitle: Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress
Creators: Tanja Hadzic - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Nükhet Aykin-Burns
Yueming Zhu
Mitchell C Coleman
Katie Leick
Geraldine M Jacobson
Douglas R Spitz
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.48(8), pp.1024-1033
DOI: 10.1016/j.freeradbiomed.2010.01.018
PMID: 20083194
PMCID: PMC2843822
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: United States
Grant note: T32 CA078586 / NCI NIH HHS P42 ES013661 / NIEHS NIH HHS F32 CA110611 / NCI NIH HHS T32 CA078586-09 / NCI NIH HHS F32 CA110611-01 / NCI NIH HHS R01 CA133114 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01-CA100045 / NCI NIH HHS R01 CA100045-01A1 / NCI NIH HHS P30 CA086862-10S26947 / NCI NIH HHS R01 CA133114-01A1 / NCI NIH HHS T32-CA078586 / NCI NIH HHS UL1 RR024979 / NCRR NIH HHS P30-CA086862 / NCI NIH HHS F32-CA110611 / NCI NIH HHS R01-CA133114 / NCI NIH HHS P42 ES013661-01A10002 / NIEHS NIH HHS R01 CA100045 / NCI NIH HHS
Language: English
Date published: 04/15/2010
Academic Unit: Pathology; Orthopedics and Rehabilitation; Radiation Oncology
Record Identifier: 9984040378002771

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