MP81-04 ALTERATIONS OF TUMOR MICROENVIRONMENT BY NITRIC OXIDE DONOR IMPEDES CASTRATION RESISTANT PROSTATE CANCER GROWTH (2019)

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (MP81)1 Apr 2019MP81-04 ALTERATIONS OF TUMOR MICROENVIRONMENT BY NITRIC OXIDE DONOR IMPEDES CASTRATION RESISTANT PROSTATE CANCER GROWTH Himanshu Arora*, Kush Panara, Manish Kuchakulla, Shathiyah Kulandavelu, Kerry L. Burnstein, Andrew V. Schally, Joshua M. Hare, and Ranjith Ramasamy Himanshu Arora*Himanshu Arora* More articles by this author , Kush PanaraKush Panara More articles by this author , Manish KuchakullaManish Kuchakulla More articles by this author , Shathiyah KulandaveluShathiyah Kulandavelu More articles by this author , Kerry L. BurnsteinKerry L. Burnstein More articles by this author , Andrew V. SchallyAndrew V. Schally More articles by this author , Joshua M. HareJoshua M. Hare More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557423.80206.a6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Immune targeted therapy of nitric oxide synthases are being considered as a potential frontline therapeutics to treat patients diagnosed with locally advanced and metastatic prostate cancer. However, the role of nitric oxide (NO) in castration resistance prostate cancer (CPRC) is controversial because NO can increase nitrosative stress while simultaneously possessing anti-inflammatory properties. Accordingly, we tested the hypothesis that increased NO will lead to tumor suppression of CRPC through tumor micro environment. METHODS: S-Nitrosoglutathione (GSNO), an active NO donor, is a potent therapeutic agent that has been safely used in human clinical trials for pre-eclampsia and persistent pulmonary hypertension. We treated CRPC murine models and 22Rv1 cells with GSNO and studied effects of increased NO levels, mechanism of action and its long term efficacy. Animal experiments were carried out in compliance with the Institutional Animal Care and Use Committee of University of Miami. Molecular analyses were performed using standard procedures. RESULTS: S-nitrosoglutathione (GSNO), an NO donor decreased the tumor burden in murine model of CRPC by targeting tumors in a cell non autonomous manner. GSNO inhibited both the abundance of anti-inflammatory (M2) macrophages and expression of pERK indicating that tumor associated macrophages activity is influenced by NO. Additionally GSNO decreased IL-34 indicating suppression of tumor associated macrophage differentiation. Cytokine profiling of CRPC tumor grafts exposed to GSNO revealed a significant decrease in expression of G-CSF and M-CSF as compared to grafts not exposed to GSNO. We verified the durability of NO on CRPC tumor suppression by using secondary xenograft murine models. CONCLUSIONS: This study validates the significance of NO on inhibition of CRPC tumors through TME. These findings may facilitate the development of previously unidentified NO-based therapy for CRPC. Source of Funding: Supported by the American Urological Association Research Scholar Award and Stanley Glaser Award to RR. J.M.H. is supported by NIH grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, 5UM1 HL113460 and Soffer Family Foundation. Miami, FL© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e1172-e1172 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Himanshu Arora* More articles by this author Kush Panara More articles by this author Manish Kuchakulla More articles by this author Shathiyah Kulandavelu More articles by this author Kerry L. Burnstein More articles by this author Andrew V. Schally More articles by this author Joshua M. Hare More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF downloadLoading ...