Enhancement of doxorubicin toxicity following activation by NADPH cytochrome P450 reductase

Bartoszek, Agnieszka; Wolf, Charles

doi:10.1016/0006-2952(92)90201-s

Cited by 51 publications

(59 citation statements)

References 23 publications

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“…MMC, and paraquat. Some experiments to establish the ability of CYPR to activate ADR and MMC to cytotoxic products were performed by treating cells with the drugs in the presence of exogenously added puri fied CYPR, and they resulted in a marked enhancement of the cytotoxicity [14,20]. Our data demonstrated that CYPR expressed intracellularly has a reliable effect on the toxicity of these drugs.…”

Section: Discussionmentioning

confidence: 71%

“…When incubating nucleic acid with ADR, CYPR, Fc(EDTAh, and NADPH, ADR forms stable complexes with double-and single-stranded DNA, generating OH radicals which result in extensive degradation of doubleand single-stranded DNA [17], Bartoszek and Wolf [20] reported that treatment of MCF-7 cells with ADR in the presence of purified rat CYPR and NADPH resulted in a marked enhancement of ADR cytotoxicity, but no poten tiation for cell killing was observed when the ADR was incubated with CYPR and NADPH prior to addition to the cells. These results demonstrated the direct effect of CYPR on cells in the presence of ADR.…”

Section: Discussionmentioning

confidence: 99%

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Transfection of Human Cytochrome P-450 Reductase cDNA and Its Effect on the Sensitivity to Toxins

et al. 1996

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NADPH-cytochrome P-450 reductase (CYPR; EC 1.6.2.4) is an essential enzyme for the catalytic function of cytochromes and is also regarded as being implicated in drug activation. To examine whether CYPR is directly involved in the drug metabolism, a cDNA encoding human CYPR was stably transfected into Chinese hamster ovary cells. Three clonal cell lines were identified which expressed increased levels of CYPR activity (9.3- to 11.2-fold). Western blot analysis indicated that CYPR-transfectant cells contained markedly elevated levels of CYPR protein, while wild-type Chinese hamster ovary cells contained low levels. They showed 1.8- to 3.3-fold higher sensitivity to Adriamycin, 2.1- to 3.0-fold higher sensitivity to mitomycin C, and 2.9- to 4.3-fold higher sensitivity to paraquat than wild-type cells. We also studied other common-use anticancer agents: vinblastine, vincristine, VP-16, and cisplatin, but there were no differences observed in the sensitivity. This report provides the first evidence that transf ection of human CYPR into mammalian cells is concerned in the sensitivity to some drugs.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Transfection of Human Cytochrome P-450 Reductase cDNA and Its Effect on the Sensitivity to Toxins

et al. 1996

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“…These oxygenases include the P450 family enzymes involved in the metabolism of many xenobiotics [15][16][17] and endogenous compounds. CPR is the only one of the four known enzymes with both fl avine-adenine dinucleotide and fl avine mononucleotide cofactors [18][19][20] .…”

Section: Discussionmentioning

confidence: 99%

Decrease in NADPH-Cytochrome P450 Reductase Activity of the Human Heart, Liver and Lungs in the Presence of Alpha-Lipoic Acid

Dudka¹

2006

Ann Nutr Metab

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Background: NADPH-cytochrome P450 reductase (CPR) is the electron donor protein for several oxygenase enzymes located in the endoplasmic reticulum. These oxygenases include P450 family enzymes involved in the metabolism of endogenous and exogenous substances. The enzyme is involved in adriamycin (anticancer drug) and paraquat (herbicide) toxicity. CPR is a flavoprotein containing both flavine-adenine dinucleotide and flavine mononucleotide. A structural study showed the presence of several sulfhydryl (SH) groups in the CPR molecule. Some of them play a key role in catalytic activity. As α-lipoic acid contains a disulfide bond, it may react with the SH group of CPR. The aim of the study was to evaluate the effect of α-lipoic acid on human P450 reductase activity. Methods: The activity of the enzyme was determined by measuring the rate of cytochrome c reduction at 550 nm, in vitro, using heart, liver and lung microsomes. Results: The activity of CPR was decreased in all organs after addition of α-lipoic acid to the reaction mixture at concentrations of 0.01, 0.10 and 1.00 mM. The decreases in CPR activity were concentration-dependent and the sequence of relative inhibition was as follows: heart >lung >liver. However, the statistical significance of CPR activity vs. control was observed in the heart in the presence of 1.00 mM α-lipoic acid and in the lung at 0.10 and 1.00 mM α-lipoic acid. Conclusion: α-Lipoic acid decreased NADPH-CPR activity in the lung and heart. The present results are promising for future studies to obtain the most effective antidote for adriamycin and paraquat toxicity.

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“…As shown in Figure 1, SER4 CILs showed higher binding to Figure 3a (Suzuki et al, 1994). Processing of CILs might be one of the key factors for the expression of CIL cytotoxicity as it has been reported that the cytotoxicity of DOX is dependent on its reduction by cytosolic enzymes (Bartoszek and Wolf, 1992 (Drebin et al, 1985;Maier et al, 1991;our Taken together, the cytotoxic efficiency of CILs was found to be dependent not only on antigen density, but also on the cell type studied and the antigen characteristics, in particular endocytosis. These considerations are thus important in selecting useful antigens (ligand) for therapeutic application of CILs.…”

Section: Discussiomentioning

confidence: 57%

Cytotoxicity of anti-c-erbB-2 immunoliposomes containing doxorubicin on human cancer cells

Suzuki

Uno²,

Fukuda³

et al. 1995

Br J Cancer

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Sunary We have examined the selective cytotoxicity of immunoliposomes containing doxorubicin (chemoimmunoliposomes, CILs) targeting the c-erbB-2 gene product (gpl85) or gpl25. Anti-gpl85 and anti-gpl25 CHLs were prepared by conjugation of doxorubicin-containing liposomes with monoclonal antibodies SER4 (IgG) and HBJ127 (IgG) respectively. Both CILs bound to human SKBr-3 breast cancer cells and MKN-7 human gastric cancer cells, which express both antigens in high density. The IC50 of anti-gpl85CILs on protein synthesis by SKBr-3 cells was respectively 2-and 25-fold lower than that of anti-gpl25 CILs and unmodified liposomes. Furthermore, anti-gpl85 CILs significantly inhibited neither the phytohaemagglutin response of normal lymphocytes nor protein synthesis of gpl85-negative T24 bladder cancer. Quantitative analysis of cell-associated doxorubicin revealed that, compared with anti-gpl25 CILs, anti-gpl85 CILs required. respectively 4.5 and 4.3 times less doxorubicin association in SKBR-3 and MKN-7 cells, for 50% cytotoxicity. In addition, flow cytometric analysis showed that both SKBr-3 and MKN-7 internalised more anti-gpl85 CILs and processed them more efficiently than anti-gpl25 CILs. These results suggest that anti-gpl85 CILs act selectively against gpl85-expressing cancer cells and that gpl85 is a more sensitive antigen for CIL cytotoxicity associated with endocytosis activity.

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Enhancement of doxorubicin toxicity following activation by NADPH cytochrome P450 reductase

Cited by 51 publications

References 23 publications

Transfection of Human Cytochrome P-450 Reductase cDNA and Its Effect on the Sensitivity to Toxins

Transfection of Human Cytochrome P-450 Reductase cDNA and Its Effect on the Sensitivity to Toxins

Decrease in NADPH-Cytochrome P450 Reductase Activity of the Human Heart, Liver and Lungs in the Presence of Alpha-Lipoic Acid

Cytotoxicity of anti-c-erbB-2 immunoliposomes containing doxorubicin on human cancer cells

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