Disruption of the EF-2 Kinase/Hsp90 Protein Complex: A Possible Mechanism to Inhibit Glioblastoma by Geldanamycin

摘要: Glioblastoma multiforme is the most treatment-resistant brain tumor. Elongation factor-2 (EF-2) kinase (calmodulin III) a unique protein that overexpressed in glioma cell lines and human surgical specimens. Several mitogens activate this inhibitors block mitogen activation produce death. Geldanamycin (GA) benzoquinone ansamycin antibiotic disrupts Hsp90-protein interactions. Because EF-2 chaperoned by Hsp90, we investigated effects of GA on viability cells, expression protein, interaction between Hsp90 kinase. was potent inhibitor clonogenicity four cells with IC(50)s ranging from 1 to 3 nM. 17-allylamino-17-demethoxygeldanamycin (17-AAG), less toxic derivative GA, inhibited IC(50) values 13 nM C6 35 T98G cells. Treatment for 24-48 h or 17-AAG disrupted EF-2-kinase/Hsp90 interactions as measured coimmunoprecipitation, resulting decreased amount recoverable lysates. The ability inhibit growth abrogated overexpressing In addition, significantly xenograft nude mice. These studies demonstrate first time activity GAs against gliomas vitro vivo suggest destruction may be an important cytotoxic mechanism class drug.