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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2284-2291
NEOPLASIA
Novel oxime derivatives of radicicol induce erythroid
differentiation associated with preferential G1 phase
accumulation against chronic myelogenous leukemia cells through
destabilization of Bcr-Abl with Hsp90 complex
Yukimasa Shiotsu,
Leonard
M. Neckers,
Ivo Wortman,
Won G. An,
Theodor W. Schulte,
Shiro Soga,
Chikara Murakata,
Tatsuya Tamaoki, and
Shiro Akinaga
Chronic myelogenous leukemia (CML) is a clonal disorder of a
pluripotent hematopoietic stem cells characterized by a chimeric bcr-abl gene giving rise to a p210Bcr-Abl
protein with dysregulated tyrosine kinase activity. Radicicol, a
macrocyclic antifungal antibiotic, binds to the N-terminal of heat
shock protein 90 (Hsp90) and destabilizes Hsp90-associated proteins
such as Raf-1. This study investigated the effect of radicicol, novel
oxime derivatives of radicicol (KF25706 and KF58333), and herbimycin A
(HA), a benzoquinoid ansamycin antibiotic, on the growth and
differentiation of human K562 CML cells. Although KF25706 and KF58333
induced the expression of glycophorin A in K562 cells, radicicol and HA
caused erythroid differentiation transiently. Cell cycle analysis
showed that G1 phase accumulation was observed in K562
cells treated with KF58333. KF58333 treatment depleted
p210Bcr-Abl, Raf-1, and cellular tyrosine phosphorylated
proteins in K562 cells, whereas radicicol and HA showed transient
depletion of these proteins. KF58333 also down-regulated the
level of cell cycle-dependent kinases 4 and 6 and up-regulated
cell cycle-dependent kinase inhibitor p27Kip1
protein without an effect on the level of Erk and Hsp90 proteins. Immunoprecipitation analysis showed that p210Bcr-Abl formed
multiple complexes with Hsp90, some containing p23 and others Hsp70;
KF58333 treatment dissociated p210Bcr-Abl from Hsp90/p23
chaperone complexes. Furthermore, KF58333 induced apoptosis in K562
cells and administration of KF58333 prolonged the survival time of SCID
mice inoculated with K562 cells. These results suggest that KF58333 may
have therapeutic potential for the treatment of CML that involves
abnormal cellular proliferation induced by
p210Bcr-Abl.
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