298 CLUSTERIN INHIBITION USING OGX-011 SYNERGISTICALLY ENHANCES ANTITUMOR ACTIVITY OF SORAFENIB IN A HUMAN RENAL CELL CARCINOMA MODEL

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2012298 CLUSTERIN INHIBITION USING OGX-011 SYNERGISTICALLY ENHANCES ANTITUMOR ACTIVITY OF SORAFENIB IN A HUMAN RENAL CELL CARCINOMA MODEL Yuji Kusuda, Hideaki Miyake, Martin Gleave, and Masato Fujisawa Yuji KusudaYuji Kusuda Kobe, Japan More articles by this author , Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , Martin GleaveMartin Gleave Vancouver, Canada More articles by this author , and Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.357AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clusterin is expressed in a variety of malignant tumors, including renal cell carcinoma (RCC), and associated with resistance to broad-spectrum treatment. OGX-011 is a second-generation antisense oligodeoxynucleotide (ODN) currently in late-stage clinical development that potently inhibits clusterin expression and enhances the efficacy of anticancer therapies in various human cancers. The objective of this study was to investigate whether inactivation of clusterin with OGX-011 potentiates the effect of sorafenib, a novel inhibitor of multiple tyrosine kinases, in a human RCC ACHN model. METHODS Effects of a combined treatment with OGX-011 and sorafenib on ACHN cells were examined by MTT assay, DNA fragmentation assay and Western bolt analyses of proteins involved in apoptosis and signal transduction. In vivo efficacy of this combined therapy was assessed in nude mice given subcutaneous injection of ACHN cells. RESULTS We initially revealed the dose-dependent inhibition of clusterin expression in ACHN cells by treatment with OGX-011. Although clusterin expression was increased in a dose-dependent manner by sorafenib, additional treatment of ACHN cells with OGX-011 significantly blocked the upregulation of clusterin expression induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN cells, OGX-011 treatment synergistically enhanced the sensitivity of ACHN cells to sorafenib in a dose-dependent manner, reducing the IC50 by more than 50%. Characteristic apoptotic DNA ladder formation was detected after combined treatment with OGX-011 and sublethal dose of sorafenib, but not either agent alone. Furthermore, combined treatment of ACHN cells with OGX-011 and sorafenib resulted in the marked downregulation of Mcl-1, phosphorylated Akt and p44/42 MAP kinase compared with treatment with either agent alone. In vivo systemic administration of OGX-011 and sorafenib synergistically decreased the subcutaneous ACHN tumor volume compared with that of control ODN plus sorafenib. CONCLUSIONS Collectively, these findings demonstrated that clusterin helps confer a resistant phenotype of human RCC cells to sorafenib through the inhibition of apoptosis and activation of major signal transduction pathways, and that combined use of OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib in patients with advanced RCC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e121 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuji Kusuda Kobe, Japan More articles by this author Hideaki Miyake Kobe, Japan More articles by this author Martin Gleave Vancouver, Canada More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...