Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in a human bladder cancer model.

Abstract

Clusterin has been shown to be implicated in the acquisition of resistant phenotype to various kinds of apoptotic stimuli, including radiation. In bladder cancer, our previous study demonstrated that overexpression of clusterin is closely associated with disease progression and recurrence. The objective of this study was to investigate whether radiation sensitivity was enhanced by suppressing clusterin gene expression with antisense (AS) oligodeoxynucleotide (ODN) in the human bladder cancer KoTCC-1 model. Clusterin mRNA in KoTCC-1 cells after radiation was up-regulated in a dose-dependent manner; however, AS clusterin ODN treatment resulted in a marked inhibition of clusterin mRNA even after irradiation. Combined treatment of KoTCC-1 cells with radiation and AS clusterin ODN synergistically decreased plating efficacy and induced apoptotic cell death compared with either radiation or AS clusterin ODN treatment alone. In vivo systemic administration of AS clusterin ODN enhanced radiation sensitivity, significantly reducing subcutaneous KoTCC-1 tumor volume in nude mice, compared with that of mismatch control ODN. Moreover, additional administration of cisplatin to this combined regimen further achieved potential antitumor effects on subcutaneous KoTCC-1 tumor growth in nude mice. Collectively, these findings suggest that clusterin acts as a cell survival protein mediating radioresistance through the inhibition of apoptosis, and that inactivation of clusterin using AS technology might offer a novel strategy to improve the outcome of radiation therapy for patients with bladder cancer.

• Authors: Kazuki Yamanaka, Martin Gleave, Mototsugu Muramaki, Isao Hara, Hideaki Miyake
• Journal: Oncology reports (Oncol Rep) Vol. 13 Issue 5 Pg. 885-90 (May 2005) ISSN: 1021-335X [Print] Greece
• PMID: 15809754 (Publication Type: Journal Article)

Chemical References

• CLU protein, human
• Clu protein, mouse
• Clusterin
• Glycoproteins
• Molecular Chaperones
• Neoplasm Proteins
• Oligonucleotides, Antisense
• RNA, Messenger
• Cisplatin

Topics

• Animals
• Apoptosis (genetics)
• Cell Line, Tumor
• Cisplatin (therapeutic use)
• Clusterin
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycoproteins (genetics)
• Humans
• Mice
• Mice, Nude
• Molecular Chaperones (genetics)
• Neoplasm Proteins (genetics)
• Oligonucleotides, Antisense (pharmacology)
• RNA, Messenger (genetics)
• Transcription, Genetic (drug effects)
• Transplantation, Heterologous
• Urinary Bladder Neoplasms (drug therapy, genetics, radiotherapy)