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Effects of mTOR Inhibitor Everolimus (RAD0011) On Bladder Cancer Cells

Chiong, Edmund and Lee, I-Ling and Dadbin, Ali and Sabichi, Anita L and Harris, Loleta and Urbauer, Diana and McConkey, David and Grossman, H Barton and Imark, Esther (2011) Effects of mTOR Inhibitor Everolimus (RAD0011) On Bladder Cancer Cells. Clinical Cancer Research, 17 (9). pp. 2863-2873. ISSN 1078-0432

Abstract

Purpose: We investigated the effect of the mTOR inhibitor everolimus (RAD001) on human bladder cancer cells in vitro and in vivo.
Experimental Design: The UM-UC-3, UM-UC-6, UM-UC-9 and UM-UC-14 cell lines were treated at different concentrations of RAD001. Growth effect was assessed by crystal violet assays at different time courses, with or without RAD001 re-dosing. Flow cytometric cell cycle analyses, propidium iodide exclusion and annexin V assays were performed. Tritium radiolabeled leucine incorporation and western blot assays were also performed. In vivo experiments were performed using nude mice subcutaneously implanted with UM-UC-3, UM-UC-6, and UM-UC-9 and treated with orally RAD001 or placebo. Tumors were harvested for immunohistochemistry.
Results: The RAD001 treated bladder cancer cells showed transient growth inhibition in a dosedependent manner, with growth inhibition augmented by re-treatment after 3 days. UMUC-14 was most sensitive to RAD001 therapy while UM-UC-9 was least sensitive.RAD001 showed G1 growth phase arrest only after prolonged treatment in sensitive cell lines. There was no evidence of apoptosis. Significant tumor growth inhibition compared to controls was shown in murine subcutaneous tumors from UM-UC-3, UM-UC-6, and UM-UC-9 cell lines. Protein synthesis inhibition via S6K and 4EBP1 pathway appears to be the main mechanism of bladder cancer cell growth inhibition by RAD001. However, inhibition of angiogenesis was the predominant mechanism for UM-UC-9 cells.
Conclusions: The mTOR inhibitor RAD001 inhibits growth of bladder cancer cells in vitro. RAD001 is effective in treating bladder cancer in vivo, in spite of heterogeneity of tumor response in vitro.

Item Type: Article
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1606

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