Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance

Brian L. Samuels, Judith L. Murray, Marvin B. Cohen, Ahmad Safa, Birandra K. Sinha, Alan J. Townsend, Michael A. Beckett, Ralph R. Weichselbaum

Research output: Contribution to journalArticle

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Abstract

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lives from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N′-β-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.

Original languageEnglish (US)
Pages (from-to)521-527
Number of pages7
JournalCancer Research
Volume51
Issue number2
StatePublished - Jan 15 1991
Externally publishedYes

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Glutathione Peroxidase
Sarcoma
Doxorubicin
Cell Line
P-Glycoprotein
Glutathione
Buthionine Sulfoximine
Daunorubicin
Vinblastine
Electron Spin Resonance Spectroscopy
Multiple Drug Resistance
Selenium
Verapamil
Drug Resistance
Hydroxyl Radical
Peroxidase
Reactive Oxygen Species
Neoplasms
Spectrum Analysis
Complementary DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Samuels, B. L., Murray, J. L., Cohen, M. B., Safa, A., Sinha, B. K., Townsend, A. J., ... Weichselbaum, R. R. (1991). Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. Cancer Research, 51(2), 521-527.

Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. / Samuels, Brian L.; Murray, Judith L.; Cohen, Marvin B.; Safa, Ahmad; Sinha, Birandra K.; Townsend, Alan J.; Beckett, Michael A.; Weichselbaum, Ralph R.

In: Cancer Research, Vol. 51, No. 2, 15.01.1991, p. 521-527.

Research output: Contribution to journalArticle

Samuels, BL, Murray, JL, Cohen, MB, Safa, A, Sinha, BK, Townsend, AJ, Beckett, MA & Weichselbaum, RR 1991, 'Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance', Cancer Research, vol. 51, no. 2, pp. 521-527.
Samuels BL, Murray JL, Cohen MB, Safa A, Sinha BK, Townsend AJ et al. Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. Cancer Research. 1991 Jan 15;51(2):521-527.
Samuels, Brian L. ; Murray, Judith L. ; Cohen, Marvin B. ; Safa, Ahmad ; Sinha, Birandra K. ; Townsend, Alan J. ; Beckett, Michael A. ; Weichselbaum, Ralph R. / Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. In: Cancer Research. 1991 ; Vol. 51, No. 2. pp. 521-527.
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AU - Townsend, Alan J.

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AU - Weichselbaum, Ralph R.

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AB - Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lives from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N′-β-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.

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