Abstract
PurposeRadiation therapy for invasive bladder cancer allows for organ preservation but toxicity and local control remain problematic. As such, improving efficacy of treatment requires radiosensitization of tumor cells. The aim of study is to investigate if the mammalian Target of Rapamycin (mTOR), a downstream kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT survival pathway, may be a target for radiation sensitization.Experimental DesignClonogenic assays were performed using 6 bladder cancer cell lines (UM-UC3, UM-UC5, UM-UC6, KU7, 253J-BV, and 253-JP) in order to examine the effects of ionizing radiation (IR) alone and in combination with RAD001, an mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In vivo, athymic mice were subcutaneously injected with 2 bladder cancer cell lines. Treatment response with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9Gy = 3Gy×3), and combination of RAD001 and IR was followed over 4 weeks. Tumor weight was measured at experimental endpoint.ResultsClonogenic assays revealed that in all bladder cell lines tested, an additive effect was observed in the combined treatment when compared to either treatment alone. Our data indicates that this effect is due to arrest in both G1 and G2 phases of cell cycle when treatments are combined. Furthermore, our data show that this arrest is primarily regulated by changes in levels of cyclin D1, p27 and p21 following treatments. In vivo, a significant decrease in tumor weight was observed in the combined treatment compared to either treatment alone or control.ConclusionsAltering cell cycle by inhibiting the mTOR signaling pathway in combination with radiation have favorable outcomes and is a promising therapeutic modality for bladder cancer.
Highlights
Bladder cancer is a very prevalent disease in North America
We recently demonstrated that a panel of nine bladder cancer cell lines exhibits relative differences in their RAD001 sensitivity and RAD001 treatment resulted in relative differences in mammalian Target of Rapamycin (mTOR) inhibition and growth arrest, as monitored by MTT assays
In this study looking at the effects of combined treatments (RAD001 and radiation), clonogenic assays was used to classify the six cell lines tested according to their relative sensitivities to ionizing radiation (IR) to various doses of radiation (Fig. 1A)
Summary
Bladder cancer is a very prevalent disease in North America. Radical cystectomy which consists of the complete removal of the bladder, remains the ‘‘gold standard’’ treatment for invasive bladder cancer [2]. Radiation therapy is an attractive alternative as it preserves the bladder and allows for normal urinary and sexual functions [3]. The lack of local control of the disease as well as the significant toxicity that is associated with radiation therapy remains problematic [4,5,6]. Chemoradiation studies remain associated with suboptimal local control of disease and decrease survival compared with radical surgery. There is an imperative need to increase radiosensitization of bladder cancer to increase efficacy by improving local control of disease and allowing for dose reduction to decrease toxicity of radiation therapy
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