Effects of mTOR Inhibitor Everolimus (RAD001) on Bladder Cancer Cells

被引：59

作者：

Chiong, Edmund ^{[4
]}

Lee, I-Ling ^{[1
]}

Dadbin, Ali ^{[1
]}

Sabichi, Anita L. ^{[2
]}

Harris, Loleta ^{[1
]}

Urbauer, Diana ^{[3
]}

McConkey, David J. ^{[1
]}

Dickstein, Rian J. ^{[1
]}

Cheng, Tiewei ^{[1
]}

Grossman, H. Barton ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Urol, Unit 1373, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Div Quantitat Sci, Houston, TX 77030 USA

[4] Natl Univ Hlth Syst, Dept Urol, Singapore, Singapore

来源：

CLINICAL CANCER RESEARCH | 2011年 / 17卷 / 09期

基金：

美国国家卫生研究院;

关键词：

MAMMALIAN TARGET; NATURAL-HISTORY; RAPAMYCIN; THERAPY; PATHWAY; GROWTH; TUMORS; PTEN; DOXORUBICIN; ACTIVATION;

D O I：

10.1158/1078-0432.CCR-09-3202

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: We investigated the effect of the mTOR inhibitor RAD001 (everolimus) on human bladder cancer (BC) cells in vitro and in vivo. Experimental Design: The effect of RAD001 on the growth of UM-UC-3, UM-UC-6, UM-UC-9, and UM-UC-14 BC cells were assessed by crystal violet and [(3)H] thymidine incorporation assays. Flow cytometric cell-cycle analyses were done to measure the apoptotic cell fraction. Protein synthesis was measured using tritium-labeled leucine incorporation assays. The effects of RAD001 on the mTOR pathway were analyzed by Western blotting. To test the effects of RAD001 in vivo, UM-UC-3, UM-UC-6, and UM-UC9 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with RAD001 or placebo. Tumors were harvested for immunohistochemical analysis. Results: In vitro, RAD001 transiently inhibited BC cell growth in a dose-dependent manner. This effect was augmented by re-treatment of cells after 3 days. UM-UC-14 cells were the most sensitive to RAD001, whereas UM-UC-9 cells were the least sensitive. After re-treatment with RAD001, only sensitive cell lines showed G(1)-phase arrest, with no evidence of apoptosis. RAD001 significantly inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of protein synthesis through the S6K and 4EBP1 pathways seems to be the main mechanism for the RAD001-induced growth inhibition. However, inhibition of angiogenesis was the predominant mechanism of the effect of RAD001 on UM-UC-9 cells. Conclusions: The mTOR inhibitor RAD001 inhibits growth of BC cells in vitro. RAD001 is effective in treating BC tumors in an in vivo nude mouse model despite the heterogeneity of in vitro responses. Clin Cancer Res; 17(9); 2863-73. (C) 2011 AACR.

引用

页码：2863 / 2873

页数：11

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