Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism

Melissa A. Fath, Iman M Ahmad, Carmen J. Smith, Jacquelyn Spence, Douglas R. Spitz

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Purpose: Cancer cells (relative to normal cells) show increased steady-state levels of hydroperoxides that are compensated by increased glucose and hydroperoxide metabolism. The current study determined whether inhibitors of glucose and hydroperoxide metabolism could induce chemoradiosensitization by enhancing oxidative stress in lung cancer cells. Experimental Design: A549 and NCI-H292 human lung carcinoma cells were treated with 2-deoxy-d-glucose (2DG) combined with carboplatin + ionizing radiation (IR). Lung cancer cells were further sensitized with inhibitors of glutathione (GSH)- and thioredoxin (Trx)-dependent metabolism [buthionine sulfoximine (BSO) and auranofin, respectively] in vitro and in vivo. Results: When 2DG was combined with carboplatin + IR, clonogenic cell killing was enhanced in A549 and NCI-H292 cells, and this combination was more effective than paclitaxel + carboplatin + IR. The thiol antioxidant (N-acetylcysteine, NAC) was capable of protecting cancer cells from 2DG + carboplatin-induced cell killing. Simultaneous treatment of cancer cells with BSO and auranofin, at doses that were not toxic as single agents, also enhanced lung cancer cell killing and sensitivity to 2DG + carboplatin. This treatment combination also increased oxidation of both GSH and Trx, which were inhibited by NAC. Mice treated with auranofin + BSO showed no alterations in circulating leukocytes or red blood cells. Xenograft lung tumor growth in mice was more effectively inhibited by treatment with auranofin + BSO + carboplatin than animals treated with carboplatin or auranofin + BSO alone. Conclusions: These results show in vitro and in vivo that simultaneous inhibition of GSH and Trx metabolism can effectively inhibit lung cancer cell growth and induce chemosensitization by a mechanism that involves thiol-mediated oxidative stress.

Original languageEnglish (US)
Pages (from-to)6206-6217
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number19
DOIs
StatePublished - Oct 1 2011

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Thioredoxins
Carboplatin
Glutathione
Lung Neoplasms
Auranofin
Buthionine Sulfoximine
Glucose
Ionizing Radiation
Hydrogen Peroxide
Acetylcysteine
Sulfhydryl Compounds
Neoplasms
Oxidative Stress
Lung
Poisons
Growth
Paclitaxel
Heterografts
Leukocytes
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism. / Fath, Melissa A.; Ahmad, Iman M; Smith, Carmen J.; Spence, Jacquelyn; Spitz, Douglas R.

In: Clinical Cancer Research, Vol. 17, No. 19, 01.10.2011, p. 6206-6217.

Research output: Contribution to journalArticle

Fath, Melissa A. ; Ahmad, Iman M ; Smith, Carmen J. ; Spence, Jacquelyn ; Spitz, Douglas R. / Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 19. pp. 6206-6217.
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