부산대학교 도서관

Chromosome maintenance protein 1 (CRIV11) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRMI-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRIV11 and block the function of this protein have been réintroduction cently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT- 185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5-fold increase), cellcycle arrest, and myeloid differentiation in AIVIL cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3- ITD and wild-type cell lines was observed. Finally, using the FLTS-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT- 276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P<.01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPTSINE in AML. [ABSTRACT FROM AUTHOR]