2010 Fiscal Year Final Research Report
Intravesical administration of heat shock protein 90-survivin complex inhibitor suppresses the growth of non-invasive bladder cancer
Project/Area Number |
21791492
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Single-year Grants |
Research Field |
Urology
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
YANO Akihiro Tokyo Medical and Dental University, 医学部附属病院, 助教 (10333014)
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Project Period (FY) |
2009 – 2010
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Keywords | 膀胱癌 / Hsp90 / サバイビン / 膀胱内注入療法 |
Research Abstract |
INTRODUCTION AND OBJECTIVE: Heat shock protein (Hsp) 90 is a molecular chaperone that is involved in signaling pathways for cell proliferation and/or survival of cancer cells. Hsp90 is highly expressed in 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 survivin-Hsp90 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 ass
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ay 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. 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-survivin complex inhibitor 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. Less
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Research Products
(1 results)