Research Papers:

Targeting Enox1 in tumor stroma increases the efficacy of fractionated radiotherapy

Clayton A. Smith _, Stacey Mont, Geri Traver, Konjeti R. Sekhar, Peter A. Crooks and Michael L. Freeman

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Oncotarget. 2016; 7:77926-77936. https://doi.org/10.18632/oncotarget.12845

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Clayton A. Smith1,2, Stacey Mont1, Geri Traver1, Konjeti R. Sekhar1, Peter A. Crooks3, Michael L. Freeman1

1Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA

2Current Address: Department of Radiation Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA

3Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

Correspondence to:

Clayton A. Smith, email: [email protected]

Michael L. Freeman, email: [email protected]

Keywords: radiation therapy, Enox1, xenograft, tumor stroma, endothelial

Received: June 07, 2016    Accepted: October 14, 2016    Published: October 24, 2016


The goal of this investigation was to clarify the question of whether targeting Enox1 in tumor stroma would synergistically enhance the survival of tumor-bearing mice treated with fractionated radiotherapy. Enox1, a NADH oxidase, is expressed in tumor vasculature and stroma. However, it is not expressed in many tumor types, including HT-29 colorectal carcinoma cells. Pharmacological inhibition of Enox1 in endothelial cells inhibited repair of DNA double strand breaks, as measured by γH2AX and 53BP1 foci formation, as well as neutral comet assays. For 4 consecutive days athymic mice bearing HT-29 hindlimb xenografts were injected with a small molecule inhibitor of Enox1 or solvent control. Tumors were then administered 2 Gy of x-rays. On day 5 tumors were administered a single ‘top-up’ fraction of 30 Gy, the purpose of which was to amplify intrinsic differences in the radiation fractionation regimen produced by Enox1 targeting. Pharmacological targeting of Enox1 resulted in 80% of the tumor-bearing mice surviving at 90 days compared to only 40% of tumor-bearing mice treated with solvent control. The increase in survival was not a consequence of reoxygenation, as measured by pimonidazole immunostaining. These results are interpreted to indicate that targeting of Enox1 in tumor stroma significantly enhances the effectiveness of 2 Gy fractionated radiotherapy and identifies Enox1 as a potential therapeutic target.

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