MP92-08 CLUSTERIN INHIBITION USING OGX-011 SYNERGISTICALLY ENHANCES ANTITUMOUR ACTIVITY OF AXITINIB IN A HUMAN RENAL CELL CARCINOMA MODEL

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2016MP92-08 CLUSTERIN INHIBITION USING OGX-011 SYNERGISTICALLY ENHANCES ANTITUMOUR ACTIVITY OF AXITINIB IN A HUMAN RENAL CELL CARCINOMA MODEL Satoshi Imai, Hideaki Miyake, Martin Gleave, and Masato Fujisawa Satoshi ImaiSatoshi Imai More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , Martin GleaveMartin Gleave More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2641AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clusterin is expressed in various malignant tumors, including renal cell carcinoma (RCC), and associated with resistance to a wide variety of therapeutic stimuli. 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 several types of human cancer. The objective of this study was to investigate whether inactivation of clusterin with OGX-011 enhances the effect of axitinib, a potential vascular endothelial growth (VEGF)-targeted agent, in a human RCC ACHN model. METHODS Effects of a combined treatment with OGX-011 and axitinib on ACHN cells were examined by MTT assay, DNA fragmentation assay and Western bolt analyses of proteins involved in apoptosis, signal transduction and autophagy. In vivo efficacy of this combined therapy was assessed in nude mice given subcutaneous injection of ACHN cells. RESULTS Although clusterin expression was increased by axitinib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by axitinib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to axitinib, reducing the IC50 by more than 50%. Apoptotic changes were intensively detected in ACHN cells after combined treatment with OGX-011 and a sublethal dose of axitinib, but not either agent alone. Furthermore, this combined treatment resulted in the marked downregulation of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN cells compared with treatment with either agent alone, while the expression levels of Bcl-2, Bcl-xL and p53 after the combined treatment were significantly upregulated compared with those after treatment with either agent alone. In vivo systemic administration of OGX-011 plus axitinib significantly decreased the ACHN tumour volume compared with control ODN plus axitinib. Although no significant differences in the proportions of cells positive for Ki-67 immunostaining or TUNEL assay between the group treated with OGX-011 and that with control ODN, the inhibition of cell proliferation and induction of apoptosis in ACHN tumors treated with OGX-011 and axitinib were markedly remarkable than those in ACHN tumors treated with control ODN and axitinib. CONCLUSIONS Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of axitinib on RCC by inducing apoptosis and inactivating major signal transduction pathways. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1164-e1165 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Satoshi Imai More articles by this author Hideaki Miyake More articles by this author Martin Gleave More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...