Abstract 4250: Nitric oxide synthase activity and its modulation in the treatment of colorectal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn's Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is uncoupled Nitric Oxide Synthase. Under non-inflammatory conditions NOS generates Nitric Oxide. However, in an inflammatory environment, such as the oxidative tumor microenvironment, NOS's cofactor tetrahydrobiopterin (BH4) is oxidized to dihydrobiopterin (BH2). NOS bound to BH2 is said to be uncoupled and produces superoxide O2- and peroxyinitrite (ONOO-). Previous work in our and other's labs have shown that increased production of ROS/RNS leads to the activation of pro-inflammatory/proliferative molecules such as NFκB, Stat3, β-Catenin and Akt. NOS can be re-coupled by supplementing cells and animals with BH4 or its precursor Sepiapterin (SP). Herein Wwe have shownshow that by recoupling NOS with SP in HCT116, Caco-2 and HT29 cells, decreased tumor cell proliferation, increased β-Catenin degradation and decreased Akt activity. We have also seen increased tumor cell death measured via by in vitro clonogenic assays, as well decreased metabolic uptake in AOM/DSS induced colorectal cancer in vivo measured via by F18Deoxy-Glucose PET imaging. We believe by recoupling NOS both in vivo and in vitro we are modulatingion Wnt signaling via Akt and GSK-3β. Further studies are needed to elucidate the mechanism of decreased Akt activity and the downstream effectors of Wnt signaling which are affected by NOS recoupling. Lastly, we wish to combine radiation therapy with Sepiapterin SP to determine if the combination of these therapies can increase tumor cell deathincrease tumor control. Citation Format: Asim Alam, Chris Rabender, Li Wang, Sundaresan Gobalakrishnan, Jamal Zweit. Nitric oxide synthase activity and its modulation in the treatment of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4250. doi:10.1158/1538-7445.AM2014-4250