title: Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model.
abstract: BACKGROUND
  The objective of this study was to investigate whether the therapeutic activity of sorafenib could be enhanced by combining with OGX-011, an antisense oligodeoxynucleotide (ODN) targeting clusterin, in renal cell carcinoma (RCC).
  
  
  METHODS
  We investigated the effects of combined treatment with OGX-011 and sorafenib on a human RCC ACHN model both in vitro and in vivo.
  
  
  RESULTS
  Although clusterin expression was increased by sorafenib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to sorafenib, reducing the IC(50) by >50%. Apoptotic changes were intensively detected in ACHN after combined treatment with OGX-011 and a sublethal dose of sorafenib, 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 compared with treatment with either agent alone. In vivo systemic administration of OGX-011 plus sorafenib significantly decreased the ACHN tumour volume compared with control ODN plus sorafenib.
  
  
  CONCLUSIONS
  Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib on RCC by inducing apoptosis and inactivating major signal transduction pathways.
authors.affiliation: Division of Urology, Kobe University Graduate school of Medicine, Chuo-ku, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kususda
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: M E
authors.initials: ME
authors.lastname: Gleave
authors.forename: M
authors.initials: M
authors.lastname: Fujisawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051152:Clusterin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077157:Sorafenib; D013873:Thionucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D001557:Benzenesulfonates; D051152:Clusterin; C503781:OGX-011; D016376:Oligonucleotides, Antisense; D010671:Phenylurea Compounds; D011725:Pyridines; D013873:Thionucleotides; D009536:Niacinamide; D000077157:Sorafenib