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Impairment of glioma stem cell survival and growth by a novel inhibitor for Survivin/Ran protein complex.

Al's Comment:

 This is fascinating on 2 levels... first - they describe a protien complex Survivin-Ran  which may be responsible for making GBM cells resistent to Temodar, then they use a new method to create drugs using computer modeling - the start with the target  then engineer a drug on a computer that would attach to the protien complex - and then actually make the drug.  And in the test tube it actually works.  This is way too early to help us - but something to keep an eye on.


Posted on: 12/20/2012

Clin Cancer Res. 2012 Dec 18. [Epub ahead of print]
 
Impairment of glioma stem cell survival and growth by a novel inhibitor for Survivin/Ran protein complex.
 
Guvenc H, Pavlyukov MS, Kurt H, Joshi K, Banasavadi-Siddegowda YK, Mao P, Hong C, Yamada R, Kwon CH, Bhasin D, Chettiar SN, Kitange GJ, Park IH, Sarkaria JN, Li C, Shakhparonov MI, Nakano I.
NEUROLOGICAL SURGERY, OHIO STATE UNIVERSITY.
 
Abstract
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 qRT-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With 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 performed 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 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 demonstrated that Survivin expression is significantly increased in recurrent GBM than newly-diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment.
 
CONCLUSIONS: 
Disruption of Survivin-Ran complex by LLP-3 abolishes GSCs' survival and growth both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM.
 
 PMID: 23251006 [PubMed - as supplied by publisher] 
 

 


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