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Advances in Breast Cancer Therapy Using Nitric Oxide and Nitroxyl Donor Agents

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Redox-Active Therapeutics

Abstract

Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory findings regarding its role in cancer biology. With greater understanding, it is now well established that the biphasic effects of NO are concentration dependent. Low flux of NO less than 10 nM is essential for normal physiological functions such as vascular maintenance. Intermediate levels of NO higher than 100 nM affect critical pathways that lead to tumor progression, whereas higher flux NO (>800 nM) induces tumor regression. Nitric oxide synthase (NOS) enzymes, particularly inducible NOS (iNOS), have often been shown to exert both pro- and antitumor effects. The elucidation of the involvement of intermediate NO flux generated by iNOS during cancer progression has led to the rapid development of several classes of NOS inhibitors with potent therapeutic effects. In contrast, the generation of higher NO flux in the tumor microenvironment tips the balance to favor cytostasis and cell killing. Toward this end, several classes of NO donors (e.g., nitrate esters, S-nitrosothiols, and diazeniumdiolates) have been examined both in vitro and in vivo and have demonstrated vast potential as chemotherapeutic agents as well. Recently, nitroxyl (HNO) has emerged as a key player with promising therapeutic potential as it exhibits properties that are often orthogonal to NO. Significant potential of HNO in the treatment of cardiovascular disease, clinical usage as an alcohol deterrent agent, and chemotherapeutic activity are only a few of its properties that have recently been explored. In this chapter, we briefly review some of the key pathways/chemical modifications by which NO and HNO exert their physiological outcome in cancer biology. NOS inhibition and utilization of NO donors as effective therapeutic options for NO-based therapy, HNO donors and their utilization as chemo drugs, and lastly NO/HNO-based hybrid drugs are discussed to show the therapeutic depth and potential for NO and HNO in cancer treatment.

The original version of this chapter was revised. An erratum to this chapter can be found at DOI 10.1007/978-3-319-30705-3_31

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-3-319-30705-3_31

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Acknowledgments

This work was supported in part by the Intramural Research Program of the NIH, Cancer and Inflammation Program.

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Authors and Affiliations

  1. Cancer and Inflammation Program, NCI-Frederick, 1050 Boyles St, Bldg 567 Rm 253, Frederick, MD, 21702, USA

    Debashree Basudhar, David A. Wink & Lisa A. Ridnour

  2. Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd, Tucson, AZ, 85721, USA

    Katrina M. Miranda

Authors
  1. Debashree Basudhar
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  2. Katrina M. Miranda
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  3. David A. Wink
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  4. Lisa A. Ridnour
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Correspondence to Lisa A. Ridnour .

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Editors and Affiliations

  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Basudhar, D., Miranda, K.M., Wink, D.A., Ridnour, L.A. (2016). Advances in Breast Cancer Therapy Using Nitric Oxide and Nitroxyl Donor Agents. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_15

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