PD44-11 THERAPEUTIC POTENTIAL OF NITRIC OXIDE AGAINST NEUROENDOCRINE PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (PD44)1 Sep 2021PD44-11 THERAPEUTIC POTENTIAL OF NITRIC OXIDE AGAINST NEUROENDOCRINE PROSTATE CANCER Fabio Frech, Omar Rosete, Khushi Shah, Fakiha Firdaus, Joshua Hare, Ranjith Ramasamy, and Himanshu Arora Fabio FrechFabio Frech More articles by this author , Omar RoseteOmar Rosete More articles by this author , Khushi ShahKhushi Shah More articles by this author , Fakiha FirdausFakiha Firdaus More articles by this author , Joshua HareJoshua Hare More articles by this author , Ranjith RamasamyRanjith Ramasamy More articles by this author , and Himanshu AroraHimanshu Arora More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002058.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. The underlying mechanisms and effective therapies against NEPC are largely underexplored. We showed that S-nitrosoglutathione (GSNO), an NO donor, reduced CRPC tumor burden by targeting the tumor microenvironment (TME). In the present study, we evaluated the impact of increased nitric oxide on NEPC reduction. We hypothesized that increased nitric oxide reduces NEPC tumor burden by suppressing NEPC TME. METHODS: Cell proliferation assay (MTT) was performed using H660 cells (NEPC cells) in the presence of increasing concentration of GSNO (from 0, 5, 10, 25, 50, 100, 200, and 500 uM respectively). Expression of neuroendocrine and proliferative markers (chromogranin A, synaptophysin, and pERK) was checked at RNA and protein levels after treating H660 cells with increasing concentrations of GSNO (from 0, 25, 50, 100, 200, and 500uM respectively). For in-vivo experiments, castrated SCID mice were grafted with H660 cells (3 million) to generate NEPC murine models. Once tumors became palpable, the animals were divided into two groups. Group 1 received vehicle control and group 2 received GSNO treatment at the dosage of 10 mg/kg/day intraperitoneally (IP). Treatment was performed daily for two weeks and tumor growth was monitored until tumor reached 1000 mm3 size. Subsequently, tumors and blood were extracted; proteins were harvested from the tumors to study the expression of neuroendocrine markers and markers of cancer progression. 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. GraphPad Prism (GraphPad Software) was used for statistical analysis. All data were presented as the means±SEM. The statistical significance between two groups was estimated by unpaired two-tailed t test. RESULTS: Cell proliferation assay showed that increase NO levels suppresses H660 cell proliferation with increasing doses. In-vivo results showed that treatment with GSNO in castrated SCID mice treated with H660 cells showed a significant decrease (p<0.05) in tumor volume compared to the mice which received PBS. Proteins from the tumors showed that GSNO induces a reduction in chromogranin A and synaptophysin (neuroendocrine markers) compared to control. Moreover, immunohistochemistry results showed a significant reduction in synaptophysin, PSA and CD206 levels. CONCLUSIONS: This study shows that GSNO decreases NEPC tumor volume and H660 cell proliferation. GSNO is known to reduce tumor burden in CRPC through interaction with the TME. Further studies investigating the mechanism of effect of nitric oxide in NEPC through the targeting of the TME are in process. Source of Funding: Clinician Scientist Development award from American Cancer Society to RR and Research Scholar Award from American Urological Association to HA © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e741-e741 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fabio Frech More articles by this author Omar Rosete More articles by this author Khushi Shah More articles by this author Fakiha Firdaus More articles by this author Joshua Hare More articles by this author Ranjith Ramasamy More articles by this author Himanshu Arora More articles by this author Expand All Advertisement Loading ...