Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001

被引：32

作者：

Wedel, Steffen ^{[1
]}

Hudak, Lukasz ^{[1
]}

Seibel, Jens-Michael ^{[1
]}

Juengel, Eva ^{[1
]}

Tsaur, Igor ^{[1
]}

Wiesner, Christoph ^{[1
]}

Haferkamp, Axel ^{[1
]}

Blaheta, Roman A. ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Dept Urol, D-60590 Frankfurt, Germany

来源：

LIFE SCIENCES | 2011年 / 88卷 / 9-10期

关键词：

HDAC; mTOR; Prostate carcinoma; Cyclins; Cell cycle; RENAL-CELL CARCINOMA; DOWN-REGULATION; MAMMALIAN TARGET; CYCLIN D1; IN-VITRO; KAPPA-B; EXPRESSION; PATHWAY; PHOSPHORYLATION; PROLIFERATION;

D O I：

10.1016/j.lfs.2010.12.017

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Aims: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth. Main methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined. Key findings: Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells. Significance: The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：418 / 424

页数：7

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