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Intravesical administration of heat shock protein 90-survivin complex inhibitor suppresses the growth of non-invasive bladder cancer

热休克蛋白90-生存素复合物抑制剂膀胱内给药抑制非浸润性膀胱癌的生长

基本信息

批准号：
21791492
负责人：
YANO Akihiro
金额：
$ 2.66万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21791492/
关键词：
膀胱癌 Hsp90 サバイビン膀胱内注入療法 Survivin

项目摘要

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 … More 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

简介和目的：热休克蛋白（Hsp） 90是一种分子伴侣，参与细胞增殖和/或癌细胞存活的信号通路。Hsp90在癌细胞中高度表达。Survivin是Hsp90客户蛋白之一，在细胞存活调控中起重要作用。Survivin在大多数实体癌中选择性表达，在正常分化组织中很少检测到。最近，一种以survivin-Hsp90结合界面为模型的新型抗癌肽模拟物——牧羊人蛋白被生成，并被证明可以破坏survivin和其他Hsp90客户蛋白的稳定，从而导致癌细胞的大量杀伤。在本研究中，我们利用原位异种移植模型，通过膀胱内给药，研究了牧羊羊素是否可以作为一种癌症特异性分子靶向药物治疗非侵袭性膀胱癌。方法：分别采用MTS、More ay和Western blotting检测羊羊素对膀胱癌细胞增殖和客户蛋白表达的影响。以UM-UC-3荧光素酶细胞为研究对象，采用IVIS实时体内成像系统检测羊羊素膀胱内给药对UM-UC-3原位异种移植肿瘤生长的影响。结果：与未处理或对照混乱肽处理的细胞相比，用牧羊人蛋白处理膀胱癌细胞系导致剂量依赖性的细胞杀伤。用牧羊羊素处理的UM-UC-3细胞显示Hsp90客户蛋白（包括survivin和Akt）的表达缺失，细胞质中细胞色素c的水平升高。打乱后的肽不调节客户蛋白的表达。在体内，经膀胱给药羊羊素可抑制UM-UC-3原位异种移植物肿瘤的生长。与对照组相比，牧羊素处理降低了survivin和Akt的表达，并且在组织学标本中对正常膀胱尿路上皮细胞无任何毒性。结论：本研究首次表明，膀胱内给药HSP90-survivin复合物抑制剂可能是一种有效且有前景的治疗非侵袭性膀胱癌的方法，最大限度地减少对正常尿路上皮细胞的损伤。最佳的癌症治疗是在有效杀死癌细胞和同时避免损害周围正常组织之间取得良好的平衡。膀胱内给药分子靶向药物可将对健康组织的毒性降至最低，如牧羊人蛋白，可能是临床治疗非侵袭性膀胱癌患者的首选治疗方法。少