Article

CRM1 Blockade by Selective Inhibitors of Nuclear Export (SINE) attenuates Kidney Cancer Growth.

Division of Nephrology, Dept. of Internal Medicine, University of California, Davis, CA, USA, 95616; Comparative Pathology Graduate Group, University of California, Davis, CA, USA, 95616.
The Journal of urology (Impact Factor: 4.02). 10/2012; DOI: 10.1016/j.juro.2012.10.018
Source: PubMed

ABSTRACT Since renal cell carcinoma (RCC) often presents asymptomatically, patients are commonly diagnosed at the metastatic stage when treatment options are limited and survival is poor. Given that progression-free survival with current therapies for metastatic RCC is only one to two years and existing drugs are associated with a high rate of resistance, new pharmacological targets are desperately needed. We identified and evaluated the nuclear exporter protein, chromosome region maintenance protein 1 (CRM1), as a novel potential therapeutic for RCC. PURPOSE: To evaluate novel, selective inhibitors of nuclear export as potential RCC therapeutics. MATERIALS AND METHODS: Efficacy of the CRM1 inhibitors, KPT-185 and -251, was tested in several RCC cell lines and in a RCC xenograft model. Apoptosis and cell cycle arrest were quantified, and localization of p53 family proteins was assessed using standard techniques. RESULTS: KPT-185 attenuated CRM1 and showed increased cytotoxicity in RCC cells in vitro, with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused both p53 and p21 to remain primarily in the nucleus in all RCC cell lines, suggesting a mechanism of action of these compounds dependent upon tumor-suppressor protein localization. Furthermore, when administered orally in a high-grade RCC xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on-target effects and with no obvious toxicity. CONCLUSIONS: The CRM1 inhibitor family of proteins are novel therapeutic targets RCC and deserve further intensive investigation in this and other urologic malignancies.

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