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Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress.
Free Radic Biol Med. 2012 Jan 15; 52(2):436-43.FR

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 (20mM, 24h), BSO (1mM, 24h), and auranofin (500nM, 3h) 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 (15mM, 24h) 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.

Authors+Show Affiliations

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52240, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22100505

Citation

Scarbrough, Peter M., et al. "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, no. 2, 2012, pp. 436-43.
Scarbrough PM, Mapuskar KA, Mattson DM, et al. Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. Free Radic Biol Med. 2012;52(2):436-43.
Scarbrough, P. M., Mapuskar, K. A., Mattson, D. M., Gius, D., Watson, W. H., & Spitz, D. R. (2012). Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. Free Radical Biology & Medicine, 52(2), 436-43. https://doi.org/10.1016/j.freeradbiomed.2011.10.493
Scarbrough PM, et al. Simultaneous Inhibition of Glutathione- and Thioredoxin-dependent Metabolism Is Necessary to Potentiate 17AAG-induced Cancer Cell Killing Via Oxidative Stress. Free Radic Biol Med. 2012 Jan 15;52(2):436-43. PubMed PMID: 22100505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. AU - Scarbrough,Peter M, AU - Mapuskar,Kranti A, AU - Mattson,David M, AU - Gius,David, AU - Watson,Walter H, AU - Spitz,Douglas R, Y1 - 2011/11/04/ PY - 2011/03/02/received PY - 2011/10/26/revised PY - 2011/10/27/accepted PY - 2011/11/22/entrez PY - 2011/11/22/pubmed PY - 2012/5/2/medline SP - 436 EP - 43 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 52 IS - 2 N2 - 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 (20mM, 24h), BSO (1mM, 24h), and auranofin (500nM, 3h) 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 (15mM, 24h) 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/22100505/Simultaneous_inhibition_of_glutathione__and_thioredoxin_dependent_metabolism_is_necessary_to_potentiate_17AAG_induced_cancer_cell_killing_via_oxidative_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(11)01170-1 DB - PRIME DP - Unbound Medicine ER -