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Nitric Oxide Synthase Uncoupling in Tumor Progression and Cancer Therapy

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Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment

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Abstract

High levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are hallmarks of solid tumors, promoting genomic instability as well as uncontrolled proliferation. In inflammatory diseases such as diabetes, hypertension, atherosclerosis and cancer, loss of nitric oxide (NO) production is a common feature. Recent experiments demonstrated that under these conditions the relative levels of the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin (BH4), are relatively low resulting in an “uncoupled NOS” and reduced NO bioavailability and increased ROS/RNS. Similar evidence suggest that NOS uncoupling is also a critical “switching mechanism” essential for tumor progression. Furthermore, uncoupling can be exploited therapeutically as both in vitro and in vivo treatment with the BH4 precursor, Sepiapterin (SP), restores NOS coupling and shifts the balance of signaling from ROS/RNS and pro-proliferative to NO dependent and anti-proliferative pathways.

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Authors and Affiliations

  1. Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Ross B. Mikkelsen, Vasily A. Yakovlev, Christopher S. Rabender & Asim Alam

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  1. Ross B. Mikkelsen
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  2. Vasily A. Yakovlev
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  3. Christopher S. Rabender
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  4. Asim Alam
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Correspondence to Ross B. Mikkelsen .

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  1. Department of Radiation Oncology Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Mitchell S. Anscher

  2. Department of Radiation Oncology Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Kristoffer Valerie

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Mikkelsen, R.B., Yakovlev, V.A., Rabender, C.S., Alam, A. (2016). Nitric Oxide Synthase Uncoupling in Tumor Progression and Cancer Therapy. In: Anscher, M., Valerie, K. (eds) Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer, Cham. https://doi.org/10.1007/978-3-319-45594-5_6

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