The Mechanism of Radiosensitization by XXXX , a Novel Small Molecule Inhibitor of Survivin Expression, is Associated with DNA Damage Repair.

@entity1 @entity5 @entity1149 @entity67443 @entity10320 @entity10322
BACKGROUND/AIMS: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for @entity5 therapy. We investigated the effects of @entity67443 , a small molecule inhibitor of survivin expression, on the radiosensitivity of @entity1 @entity1149 ( @entity1149 ) cell lines and elucidated a relationship between the cellular localization of survivin and DNA double-strand break repair. METHODS: The cellular distribution of survivin was determined by Western blotting of subcellular fractions and by immunofluorescent staining in A549 @entity1149 cells. Radiation-induced DNA damage was evaluated based on histone H2AX phosphorylation and foci formation. The relationship between the cellular localization of survivin and DNA double-strand break repair was analyzed by Western blotting and co-immunoprecipitations. RESULTS: @entity67443 down-regulated survivin expression in @entity1149 cells in a concentration- and time-dependent manner. An in vitro clonogenic survival assay revealed that @entity67443 increased the sensitivity of @entity1149 cells to radiation. After irradiation, we observed a rapid accumulation of survivin in the nucleus. An immunofluorescent analysis of histone x03B3;-H2AX demonstrated that the inhibition of survivin expression by @entity67443 resulted in impaired DNA double-strand break repair. Co-immunoprecipitation assays using nuclear extracts revealed an interaction between survivin, @entity10320 , x03B3;-H2AX, and @entity10322 . Furthermore, S2056 autophosphorylation of @entity10322 was reduced in survivin-depleted cells. CONCLUSIONS: These results suggested that @entity67443 sensitized @entity1149 cells to radiation, at least in part by inhibiting DNA repair and enhancing apoptosis via the down-regulation of survivin expression. @entity67443 pretreatment inhibited @entity10322 autophosphorylation at S2056. Nuclear survivin was involved in DNA double-strand break repair via interactions with members of the DNA double-strand break repair machinery.
