Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin-Ran Protein Complex

被引:76
作者
Guvenc, Hacer [1 ]
Pavlyukov, Marat S. [5 ]
Joshi, Kaushal [1 ]
Kurt, Habibe [1 ]
Banasavadi-Siddegowda, Yeshavanth K. [1 ]
Mao, Ping [1 ,6 ]
Hong, Christopher [1 ]
Yamada, Ryosuke [1 ]
Kwon, Chang-Hyuk [1 ]
Bhasin, Deepak [2 ]
Chettiar, Somsundaram [2 ]
Kitange, Gaspar [4 ]
Park, In-Hee [2 ]
Sarkaria, Jann N. [4 ]
Li, Chenglong [2 ]
Shakhparonov, Mihail I. [5 ]
Nakano, Ichiro [1 ,3 ]
机构
[1] Ohio State Univ, Dept Neurol Surg, Columbus, OH 43210 USA
[2] Ohio State Univ, Div Med Chem & Pharmacognosy, Coll Pharm, Columbus, OH 43210 USA
[3] Ohio State Univ, James Comprehens Canc Ctr, Columbus, OH 43210 USA
[4] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA
[5] Shemiakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia
[6] Xi An Jiao Tong Univ, Dept Neurosurg, Affiliated Hosp 1, Sch Med, Xian 710049, Peoples R China
基金
俄罗斯基础研究基金会;
关键词
LEUCINE-ZIPPER KINASE; HUMAN GLIOBLASTOMA; EXPRESSION; APOPTOSIS; CANCER; TUMORIGENICITY; PROLIFERATION; TEMOZOLOMIDE; MICROARRAY; TARGET;
D O I
10.1158/1078-0432.CCR-12-0647
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin-Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin-Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631-42. (C) 2012 AACR.
引用
收藏
页码:631 / 642
页数:12
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