1143 INTRAVESICAL ADMINISTRATION OF HEAT SHOCK PROTEIN 90-SURVIVIN COMPLEX INHIBITOR SUPPRESSES THE GROWTH OF NON-INVASIVE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20101143 INTRAVESICAL ADMINISTRATION OF HEAT SHOCK PROTEIN 90-SURVIVIN COMPLEX INHIBITOR SUPPRESSES THE GROWTH OF NON-INVASIVE BLADDER CANCER Akihiro Yano, Yasuhisa Fujii, Hitoshi Masuda, Satoru Kawakami, and Kazunori Kihara Akihiro YanoAkihiro Yano More articles by this author , Yasuhisa FujiiYasuhisa Fujii More articles by this author , Hitoshi MasudaHitoshi Masuda More articles by this author , Satoru KawakamiSatoru Kawakami More articles by this author , and Kazunori KiharaKazunori Kihara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.642AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Heat shock protein (Hsp) 90 is a molecular chaperone that is involved in signaling pathways for cell proliferation and/or survival of cancer cells. Survivin, one of the Hsp90 client proteins, plays important roles in regulation of cellular survival. Survivin is selectively expressed in most solid cancers and is rarely detected in normal differentiated tissues. Recently, shepherdin, a novel anticancer peptidomimetic modeled on the Hsp90-survivin binding interface was generated and shown to destabilize survivin plus additional Hsp90 client proteins, causing massive killing of cancer cells. In the present study, we investigated whether shepherdin can be a cancer-specific molecular targeting agent for non-invasive bladder cancer by intravesical administration using an orthotopic xenograft model. METHODS The effects of shepherdin on bladder cancer cell proliferation and client protein expression were examined by MTS assay and Western blotting, respectively. The effects of shepherdin by intravesical administration on the growth of UM-UC-3 orthotopic xenograft tumors were determined by IVIS real-time in vivo imaging system using UM-UC-3-luciferase cells. RESULTS Treatment of the bladder cancer cell lines with shepherdin resulted in dose-dependent cell killing as compared with untreated or control scrambled peptide-treated cells. UM-UC-3 cells treated with shepherdin exhibited loss of expression of Hsp90 client proteins, including survivin and Akt, and increase in the level of cytochrome c in the cytosol. The scrambled peptide did not modulate client protein expression. In vivo, intravesical administration of shepherdin abolished the growth of UM-UC-3 orthotopic xenograft tumors (P < 0.01). Shepherdin treatment attenuated expression of survivin and Akt compared with the control group, and did not show any toxicity to normal bladder urothelial cells in the histological specimens. CONCLUSIONS This study is the first to show that intravesical administration of Hsp90-, especially survivin-targeting agent can be a potent and promising therapy for non-invasive bladder cancer minimizing damage to normal urothelial cells. Optimal cancer therapy is a fine balance between effective cancer cell killing and at the same time avoiding damage to the surrounding normal tissue. Intravesical administration of molecular targeting agent, which minimizes toxicity to healthy tissues, such as shepherdin may be the treatment of choice for patients with non-invasive bladder cancer in clinical setting. Tokyo, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e442 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Akihiro Yano More articles by this author Yasuhisa Fujii More articles by this author Hitoshi Masuda More articles by this author Satoru Kawakami More articles by this author Kazunori Kihara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...