Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation

E. G. Mimnaugh, M. A. Trush, E. Ginsburg, T. E. Gram

Research output: Contribution to journalArticle

Abstract

Rat liver microsomes have previously been utilized as a model biological system to study the activation of Adriamycin to the semiquinone free radical intermediate and the enhancement by Adriamycin of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation and oxygen consumption. Incubating rat liver microsomes with Adriamycin or other structurally similar benzanthraquinone anticancer drugs resulted in marked stimulation of NADPH-dependent lipid peroxidation. Carcinomycin and 4-demethoxydaunorubicin were considerably more potent than Adriamycin, while daunorubicin, deacetyladriamycin, N-dimethyl-adriamycin, aclacinomycin A, adriamycin 14-nicotinate, and steffimycin were approximately equipotent to Adriamycin in this test system. In contrast, lapachol, anthragallol, alkylaminoanthracenedione, mitomycin C, streptonigrin, 5-iminodaunorubicin, and the Adriamycin:DNA complex potently inhibited microsomal lipid peroxidation. Methotrexate, cyclophosphamide, 5-fluorouracil, nogalamycin, or rubidazone had little or no effect. α-Tocopherol-deficient rat heart microsomes but not control heart microsomes were susceptible to increased NADPH-dependent lipid peroxidation (up to 10-fold) when incubated with Adriamycin or other anthracycline analogs which stimulated peroxidation in liver microsomes. The rate of NADPH oxidation in the presence of microsomes was enhanced 4-fold by either Adriamycin or daunorubicin; lapachol, anthragallol, aminoanthracenedione, and 5-iminodaunorubicin at concentrations which inhibited lipid peroxidation had no effect on NADPH oxidation. NADPH:cytochrome P-450 reductase activity was unaltered by those drugs which either stimulated or inhibited peroxidation. These results suggest that although several Adriamycin-like anthracycline drugs dramatically stimulated NADPH-dependent, reactive oxygen-mediated lipid peroxidation in rat liver and heart microsomes, other quinone-containing anticancer drugs do not enhance lipid peroxidation. Interestingly, there appears to be a direct correlation between the ability of certain anthracyclines to stimulate heart or liver microsomal lipid peroxidation and the effects of these drugs in other cardiotoxicity model systems.

Original languageEnglish (US)
Pages (from-to)3574-3582
Number of pages9
JournalCancer Research
Volume42
Issue number9
StatePublished - 1982
Externally publishedYes

Fingerprint

Anthracyclines
NADP
Doxorubicin
Lipid Peroxidation
Liver
Pharmaceutical Preparations
lapachol
Liver Microsomes
Microsomes
Daunorubicin
Nogalamycin
Streptonigrin
Aclarubicin
Idarubicin
Biological Models
NADPH-Ferrihemoprotein Reductase
Tocopherols
Niacin
Mitomycin
Methotrexate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation. / Mimnaugh, E. G.; Trush, M. A.; Ginsburg, E.; Gram, T. E.

In: Cancer Research, Vol. 42, No. 9, 1982, p. 3574-3582.

Research output: Contribution to journalArticle

@article{c5e98435d84248448a13bcd923a67f3e,
title = "Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation",
abstract = "Rat liver microsomes have previously been utilized as a model biological system to study the activation of Adriamycin to the semiquinone free radical intermediate and the enhancement by Adriamycin of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation and oxygen consumption. Incubating rat liver microsomes with Adriamycin or other structurally similar benzanthraquinone anticancer drugs resulted in marked stimulation of NADPH-dependent lipid peroxidation. Carcinomycin and 4-demethoxydaunorubicin were considerably more potent than Adriamycin, while daunorubicin, deacetyladriamycin, N-dimethyl-adriamycin, aclacinomycin A, adriamycin 14-nicotinate, and steffimycin were approximately equipotent to Adriamycin in this test system. In contrast, lapachol, anthragallol, alkylaminoanthracenedione, mitomycin C, streptonigrin, 5-iminodaunorubicin, and the Adriamycin:DNA complex potently inhibited microsomal lipid peroxidation. Methotrexate, cyclophosphamide, 5-fluorouracil, nogalamycin, or rubidazone had little or no effect. α-Tocopherol-deficient rat heart microsomes but not control heart microsomes were susceptible to increased NADPH-dependent lipid peroxidation (up to 10-fold) when incubated with Adriamycin or other anthracycline analogs which stimulated peroxidation in liver microsomes. The rate of NADPH oxidation in the presence of microsomes was enhanced 4-fold by either Adriamycin or daunorubicin; lapachol, anthragallol, aminoanthracenedione, and 5-iminodaunorubicin at concentrations which inhibited lipid peroxidation had no effect on NADPH oxidation. NADPH:cytochrome P-450 reductase activity was unaltered by those drugs which either stimulated or inhibited peroxidation. These results suggest that although several Adriamycin-like anthracycline drugs dramatically stimulated NADPH-dependent, reactive oxygen-mediated lipid peroxidation in rat liver and heart microsomes, other quinone-containing anticancer drugs do not enhance lipid peroxidation. Interestingly, there appears to be a direct correlation between the ability of certain anthracyclines to stimulate heart or liver microsomal lipid peroxidation and the effects of these drugs in other cardiotoxicity model systems.",
author = "Mimnaugh, {E. G.} and Trush, {M. A.} and E. Ginsburg and Gram, {T. E.}",
year = "1982",
language = "English (US)",
volume = "42",
pages = "3574--3582",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Differential effects of anthracycline drugs on rat heart and liver microsomal reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation

AU - Mimnaugh, E. G.

AU - Trush, M. A.

AU - Ginsburg, E.

AU - Gram, T. E.

PY - 1982

Y1 - 1982

N2 - Rat liver microsomes have previously been utilized as a model biological system to study the activation of Adriamycin to the semiquinone free radical intermediate and the enhancement by Adriamycin of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation and oxygen consumption. Incubating rat liver microsomes with Adriamycin or other structurally similar benzanthraquinone anticancer drugs resulted in marked stimulation of NADPH-dependent lipid peroxidation. Carcinomycin and 4-demethoxydaunorubicin were considerably more potent than Adriamycin, while daunorubicin, deacetyladriamycin, N-dimethyl-adriamycin, aclacinomycin A, adriamycin 14-nicotinate, and steffimycin were approximately equipotent to Adriamycin in this test system. In contrast, lapachol, anthragallol, alkylaminoanthracenedione, mitomycin C, streptonigrin, 5-iminodaunorubicin, and the Adriamycin:DNA complex potently inhibited microsomal lipid peroxidation. Methotrexate, cyclophosphamide, 5-fluorouracil, nogalamycin, or rubidazone had little or no effect. α-Tocopherol-deficient rat heart microsomes but not control heart microsomes were susceptible to increased NADPH-dependent lipid peroxidation (up to 10-fold) when incubated with Adriamycin or other anthracycline analogs which stimulated peroxidation in liver microsomes. The rate of NADPH oxidation in the presence of microsomes was enhanced 4-fold by either Adriamycin or daunorubicin; lapachol, anthragallol, aminoanthracenedione, and 5-iminodaunorubicin at concentrations which inhibited lipid peroxidation had no effect on NADPH oxidation. NADPH:cytochrome P-450 reductase activity was unaltered by those drugs which either stimulated or inhibited peroxidation. These results suggest that although several Adriamycin-like anthracycline drugs dramatically stimulated NADPH-dependent, reactive oxygen-mediated lipid peroxidation in rat liver and heart microsomes, other quinone-containing anticancer drugs do not enhance lipid peroxidation. Interestingly, there appears to be a direct correlation between the ability of certain anthracyclines to stimulate heart or liver microsomal lipid peroxidation and the effects of these drugs in other cardiotoxicity model systems.

AB - Rat liver microsomes have previously been utilized as a model biological system to study the activation of Adriamycin to the semiquinone free radical intermediate and the enhancement by Adriamycin of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation and oxygen consumption. Incubating rat liver microsomes with Adriamycin or other structurally similar benzanthraquinone anticancer drugs resulted in marked stimulation of NADPH-dependent lipid peroxidation. Carcinomycin and 4-demethoxydaunorubicin were considerably more potent than Adriamycin, while daunorubicin, deacetyladriamycin, N-dimethyl-adriamycin, aclacinomycin A, adriamycin 14-nicotinate, and steffimycin were approximately equipotent to Adriamycin in this test system. In contrast, lapachol, anthragallol, alkylaminoanthracenedione, mitomycin C, streptonigrin, 5-iminodaunorubicin, and the Adriamycin:DNA complex potently inhibited microsomal lipid peroxidation. Methotrexate, cyclophosphamide, 5-fluorouracil, nogalamycin, or rubidazone had little or no effect. α-Tocopherol-deficient rat heart microsomes but not control heart microsomes were susceptible to increased NADPH-dependent lipid peroxidation (up to 10-fold) when incubated with Adriamycin or other anthracycline analogs which stimulated peroxidation in liver microsomes. The rate of NADPH oxidation in the presence of microsomes was enhanced 4-fold by either Adriamycin or daunorubicin; lapachol, anthragallol, aminoanthracenedione, and 5-iminodaunorubicin at concentrations which inhibited lipid peroxidation had no effect on NADPH oxidation. NADPH:cytochrome P-450 reductase activity was unaltered by those drugs which either stimulated or inhibited peroxidation. These results suggest that although several Adriamycin-like anthracycline drugs dramatically stimulated NADPH-dependent, reactive oxygen-mediated lipid peroxidation in rat liver and heart microsomes, other quinone-containing anticancer drugs do not enhance lipid peroxidation. Interestingly, there appears to be a direct correlation between the ability of certain anthracyclines to stimulate heart or liver microsomal lipid peroxidation and the effects of these drugs in other cardiotoxicity model systems.

UR - http://www.scopus.com/inward/record.url?scp=0019952403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019952403&partnerID=8YFLogxK

M3 - Article

C2 - 6809311

AN - SCOPUS:0019952403

VL - 42

SP - 3574

EP - 3582

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 9

ER -