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An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in
Kazuki Yamanaka1, Martin Gleave, Mototsugu Muramaki
1Department of Urology, Kobe University School of Medicine, Kobe 650-0017, Japan.
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.
Insights
Clusterin protein promotes radioresistance in bladder cancer by inhibiting apoptosis. Suppressing clusterin with antisense oligodeoxynucleotides (AS ODN) enhances radiation sensitivity and tumor reduction.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Clusterin overexpression is linked to bladder cancer progression and recurrence.
- Clusterin confers resistance to apoptotic stimuli, including radiation therapy.
Purpose of the Study:
- To investigate if suppressing clusterin gene expression enhances radiosensitivity in human bladder cancer.
- To evaluate the efficacy of antisense oligodeoxynucleotide (AS ODN) targeting clusterin in combination with radiation.
Main Methods:
- Utilized the human bladder cancer KoTCC-1 cell model.
- Administered AS clusterin ODN and radiation therapy.
- Assessed clusterin mRNA levels, cell viability (plating efficacy), and apoptosis.
- Evaluated tumor growth in vivo in nude mice with AS clusterin ODN, mismatch control ODN, and cisplatin.
Main Results:
- Radiation upregulated clusterin mRNA in a dose-dependent manner.
- AS clusterin ODN treatment inhibited clusterin mRNA expression, even after irradiation.
- Combined AS clusterin ODN and radiation synergistically reduced cell viability and induced apoptosis.
- In vivo, AS clusterin ODN enhanced radiation sensitivity, significantly reducing tumor volume.
- Combination therapy with cisplatin further improved antitumor effects.
Conclusions:
- Clusterin functions as a cell survival protein, mediating radioresistance by inhibiting apoptosis.
- Inactivating clusterin with AS technology presents a novel strategy to improve bladder cancer radiation therapy outcomes.
