Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents

Andrew P. Garner, Mark J.I. Paine, Ignacio Rodriguez-Crespo, Edwin C. Chinje, Paul Ortiz De Montellano, Ian J. Stratford, David G. Tew, C. Roland Wolf

    Research output: Contribution to journalArticle

    102 Citations (Scopus)

    Abstract

    Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin.

    Original languageEnglish
    Pages (from-to)1929-1934
    Number of pages6
    JournalCancer Research
    Volume59
    Issue number8
    Publication statusPublished - 15 Apr 1999

    Fingerprint

    tirapazamine
    Nitric Oxide Synthase
    Antineoplastic Agents
    Oxidation-Reduction
    Doxorubicin
    Vitamin K 3
    Oxidoreductases
    Enzymes
    Oxygenases
    DNA Breaks
    Cytotoxins
    Therapeutic Uses
    Nitric Oxide Synthase Type II
    Sequence Homology
    Blood Vessels
    Neoplasms
    Nitric Oxide
    Protein Isoforms
    Plasmids
    Homeostasis

    Cite this

    Garner, A. P., Paine, M. J. I., Rodriguez-Crespo, I., Chinje, E. C., De Montellano, P. O., Stratford, I. J., ... Wolf, C. R. (1999). Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents. Cancer Research, 59(8), 1929-1934.
    Garner, Andrew P. ; Paine, Mark J.I. ; Rodriguez-Crespo, Ignacio ; Chinje, Edwin C. ; De Montellano, Paul Ortiz ; Stratford, Ian J. ; Tew, David G. ; Wolf, C. Roland. / Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents. In: Cancer Research. 1999 ; Vol. 59, No. 8. pp. 1929-1934.
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    abstract = "Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin.",
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    Garner, AP, Paine, MJI, Rodriguez-Crespo, I, Chinje, EC, De Montellano, PO, Stratford, IJ, Tew, DG & Wolf, CR 1999, 'Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents', Cancer Research, vol. 59, no. 8, pp. 1929-1934.

    Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents. / Garner, Andrew P.; Paine, Mark J.I.; Rodriguez-Crespo, Ignacio; Chinje, Edwin C.; De Montellano, Paul Ortiz; Stratford, Ian J.; Tew, David G.; Wolf, C. Roland.

    In: Cancer Research, Vol. 59, No. 8, 15.04.1999, p. 1929-1934.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents

    AU - Garner, Andrew P.

    AU - Paine, Mark J.I.

    AU - Rodriguez-Crespo, Ignacio

    AU - Chinje, Edwin C.

    AU - De Montellano, Paul Ortiz

    AU - Stratford, Ian J.

    AU - Tew, David G.

    AU - Wolf, C. Roland

    PY - 1999/4/15

    Y1 - 1999/4/15

    N2 - Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin.

    AB - Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin.

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    Garner AP, Paine MJI, Rodriguez-Crespo I, Chinje EC, De Montellano PO, Stratford IJ et al. Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents. Cancer Research. 1999 Apr 15;59(8):1929-1934.