PD33-11 METABOLIC MODULATION WITH DICHLOROACETATE REVERSES THE WARBURG EFFECT AND REDUCES THE GROWTH OF CLEAR CELL RENAL CELL CARCINOMA IN VITRO AND IN VIVO

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2015PD33-11 METABOLIC MODULATION WITH DICHLOROACETATE REVERSES THE WARBURG EFFECT AND REDUCES THE GROWTH OF CLEAR CELL RENAL CELL CARCINOMA IN VITRO AND IN VIVO Adam Kinnaird, Peter Dromparis, Roxane Paulin, Bruno Saleme, Trevor Stenson, Desmond Pink, John Lewis, and Evangelos Michelakis Adam KinnairdAdam Kinnaird More articles by this author , Peter DromparisPeter Dromparis More articles by this author , Roxane PaulinRoxane Paulin More articles by this author , Bruno SalemeBruno Saleme More articles by this author , Trevor StensonTrevor Stenson More articles by this author , Desmond PinkDesmond Pink More articles by this author , John LewisJohn Lewis More articles by this author , and Evangelos MichelakisEvangelos Michelakis More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2109AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clear Cell Renal Cell Carcinoma (ccRCC) exhibits a distinct metabolic phenotype using cytoplasmic glycolysis over a suppressed glucose oxidation (GO) even in normoxia (Warburg effect; WE). This offers growth advantages including suppressed apoptosis and increased proliferation and angiogenesis. Most ccRCC have constitutively active Hypoxia Inducible Factor (HIF) (due to mutation or silencing of the von Hippel Lindau tumor factor), which induces the WE by upregulating Pyruvate Dehydrogenase kinase (PDK) and thus inhibiting Pyruvate Dehydrogenase (PDH), the gate keeping enzyme in GO. PDK inhibitors like the clinically available small molecule Dichloroacetate (DCA) have been shown to increase GO and reverse the WE, decreasing growth of solid tumors. The resulting increase in mitochondrial signals (mitochondrial-derived reactive oxygen species and α-ketoglutarate) can inhibit the redox-sensitive HIF transcriptional activity (PMID: 22614004). We hypothesized that DCA will decrease ccRCC growth even in the presence of constitutively active HIF. METHODS The 786-O ccRCC cell line was used in vitro, in ovo (cells injected into the chorioallantoic membrane of fertilized chicken eggs) and in vivo in Nu/Nu mice, following both a prevention and reversal protocol and at doses similar to those achieved in the serum of DCA treated patients. RESULTS In vitro DCA increased PDH activity and GO, increased apoptosis, decreased proliferation and decreased HIF activity, including decreasing VEGF levels. siRNA inhibition of FIH prevented most of the DCA-induced decrease in HIF activity in an α-ketoglutarate dependent manner. DCA both prevented tumor growth and decreased tumor size in the reversal protocol: in ovo mean tumor weight 74mg control, 18mg DCA, n=20 and 29 eggs respectively, p<0.05; in vivo mean tumor volume 271mm3 control, 136mm3 DCA, n=10 and 20 respectively, p<0.01. DCA significantly decreased angiogenesis in vivo, measured by lectin imaging. CONCLUSIONS DCA can reverse the WE in ccRCC and decrease tumor growth and angiogenesis even though HIF is constitutively expressed. The DCA-induced inhibition of angiogenesis may be superior to VEGF inhibitors since it suppresses the HIF axis proximal to VEGF. We suggest that DCA should be tested in early phase clinical trials in ccRCC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e713 Peer Review Report Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adam Kinnaird More articles by this author Peter Dromparis More articles by this author Roxane Paulin More articles by this author Bruno Saleme More articles by this author Trevor Stenson More articles by this author Desmond Pink More articles by this author John Lewis More articles by this author Evangelos Michelakis More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...