Journal article
Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress
Free radical biology & medicine, Vol.52(2), pp.436-443
2012
DOI: 10.1016/j.freeradbiomed.2011.10.493
PMCID: PMC3664944
PMID: 22100505
Abstract
17-Allylamino-17-demethoxygeldanamycin (17AAG) is an experimental chemotherapeutic agent believed to form free radicals
in vivo, and cancer cell resistance to 17AAG is believed to be a thiol-dependent process. Inhibitors of thiol-dependent hydroperoxide metabolism [
l-buthionine-
S,R-sulfoximine (BSO) and auranofin] were combined with the glucose metabolism inhibitor 2-deoxy-
d-glucose (2DG) to determine if 17AAG-mediated cancer cell killing could be enhanced. When 2DG (20
mM, 24
h), BSO (1
mM, 24
h), and auranofin (500
nM, 3
h) were combined with 17AAG, cell killing was significantly enhanced in three human cancer cell lines (PC-3, SUM159, MDA-MB-231). Furthermore, the toxicity of this drug combination was significantly greater in SUM159 human breast cancer cells, relative to HMEC normal human breast epithelial cells. Increases in toxicity seen with this drug combination also correlated with increased glutathione (GSH) and thioredoxin (Trx) oxidation and depletion. Furthermore, treatment with the thiol antioxidant NAC (15
mM, 24
h) was able to significantly protect from drug-induced toxicity and ameliorate GSH oxidation, Trx oxidation, and Trx depletion. These data strongly support the hypothesis that simultaneous inhibition of GSH- and Trx-dependent metabolism is necessary to sensitize human breast and prostate cancer cells to 2DG
+
17AAG-mediated killing via enhancement of thiol-dependent oxidative stress. These results suggest that simultaneous targeting of both GSH and Trx metabolism could represent an effective strategy for chemosensitization in human cancer cells.
Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing
via oxidative stress.
[Display omitted]
► Simultaneous inhibition of glutathione (GSH) and thioredoxin (TRX) sensitizes cancer cells to chemotherapy. ► Increased chemo-sensitization with inhibitors of GSH and Trx causes increased oxidative stress. ► Increased chemo-sensitization is causally related to increased oxidative stress. ► Simultaneous inhibition of GSH and Trx could be an effective strategy for chemosensitization.
Details
- Title: Subtitle
- Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress
- Creators
- Peter M Scarbrough - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52240, USAKranti A Mapuskar - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52240, USADavid M Mattson - Breast Radiation Oncology Program, Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USADavid Gius - Department of Radiation Oncology, Vanderbilt–Ingram Cancer Center, Nashville, TN 37232, USAWalter H Watson - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40292, USADouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52240, USA
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.52(2), pp.436-443
- DOI
- 10.1016/j.freeradbiomed.2011.10.493
- PMID
- 22100505
- PMCID
- PMC3664944
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 2012
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984046808702771
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