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Abstract
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.
Highlights
Radiation therapy, an important therapeutic modality for the treatment of cancer, is used to treat approximately 50% of cancer patients [1] for the purposes of localregional control of invasive disease, to reduce the risk of metastases, and for palliation [2]
RNAi and small molecule targeting of Enox1 were shown to inhibit migration of human and mouse endothelial cells and the ability of these cells to form tubule-like structures in matrigel, as well as to suppress neo-angiogenesis driven by growth of Lewis Lung Carcinoma tumor cells in a dorsal skin fold vascular window chamber [8]
Inhibition of Enox1 activity results in a profound elevation of intracellular NADH [6, 11], suppression of vascular development in zebrafish models of embryogenesis [6], inhibition of endothelial cell migration, abrogation of the ability to form tubulelike structures [8], and suppression of neoangiogenesis in dorsal skin fold vascular window chamber models [8]
Summary
An important therapeutic modality for the treatment of cancer, is used to treat approximately 50% of cancer patients [1] for the purposes of localregional control of invasive disease, to reduce the risk of metastases, and for palliation [2]. Current technology allows precise 3-dimensional irradiation of tumors that yields significant sparing of normal tissue. Even with this outstanding ability to selectively target tumor tissue, there are many instances in which tumors do not respond to radiation. Patients whose irradiated tumors recur following an initial response experience a significant reduction in median overall survival [3, 4]. RNAi and small molecule targeting of Enox were shown to inhibit migration of human and mouse endothelial cells and the ability of these cells to form tubule-like structures in matrigel, as well as to suppress neo-angiogenesis driven by growth of Lewis Lung Carcinoma tumor cells in a dorsal skin fold vascular window chamber [8]. Enox enzymatic activity links NADH metabolism to both angiogenesis and the survival of endothelial cells following DNA damage produced by ionizing radiation
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