168 DIETARY SUPPLEMENT HYMECROMONE BASED COMBINATION FOR RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (I)1 Apr 2013168 DIETARY SUPPLEMENT HYMECROMONE BASED COMBINATION FOR RENAL CELL CARCINOMA Nicolas Ortiz, Anaid Benitez, Travis Yates, and Vinata Lokeshwar Nicolas OrtizNicolas Ortiz Miami, FL More articles by this author , Anaid BenitezAnaid Benitez Miami, FL More articles by this author , Travis YatesTravis Yates Miami, FL More articles by this author , and Vinata LokeshwarVinata Lokeshwar Miami, FL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1548AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Approximately 17% of patients with renal cell carcinoma (RCC) present with metastasis upon diagnosis, rendering patients with a 5-year survival rate of 12%. Sorafenib (SF) was the first targeted therapy approved for RCC treatment, however it has modest efficacy. Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan that promotes cell proliferation, invasion and motility through membrane receptors CD44 and RHAMM. High HA expression has been correlated with cancer progression and inflammatory diseases. Hymecromone (HC) is a non−toxic dietary supplement that inhibits HA synthesis and down regulates CD44 and RHAMM mRNA. In this study we examined whether HC, SF, or their combination inhibit RCC progression. METHODS Effect of HC, SF and HC+SF on cell proliferation, cell cycle and apoptosis was examined in RCC cells (Caki−1, 786−O) and endothelial cells (HMVEC−L, HUVEC) by cell-counting, flow cytometry and Cell Death ELISA. Boyden chamber was used for motility and invasion assays. Effect on cell cycle, apoptosis, and HA receptor levels were evaluated by immunoblotting and Q−PCR. Treatment efficacy was evaluated in the Caki−1 xenograft model. RESULTS While HC (0−30 ug/ml) and SF (0−3.2 ug/ml) individually were ineffective, their combination inhibited proliferation (>95%), motility (≥60%) and invasion (≥50%) in both RCC and endothelial cells. Combination of HC+ SF induced apoptosis (>8−fold) and caused cell cycle arrest. Consistent with these results, downregulation of Cyclins A, E1, D1, phospho−cdk2, Rb, STAT3, Mcl−1 and induced PARP cleavage, and Caspase 3 activation was also seen in combination treatment. HC+SF synergistically decreased the expression of HA receptors CD44 and RHAMM at the mRNA and protein levels. The oral administration of both HC (50−100mg/kg) and SF (30mg/kg) eradicated SF-resistant Caki−1 tumors whereas individual drugs were ineffective. No serum or tissue toxicity was observed in the treated groups. CONCLUSIONS Our findings show that a novel combination of SF with HC, a non−toxic oral supplement is potentially an effective treatment strategy for metastatic RCC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e69 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicolas Ortiz Miami, FL More articles by this author Anaid Benitez Miami, FL More articles by this author Travis Yates Miami, FL More articles by this author Vinata Lokeshwar Miami, FL More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...