| Autor: |
Shiotsu, Yukimasa, Neckers, Leonard M., Wortman, Ivo, An, Won G., Schulte, Theodor W., Soga, Shiro, Murakata, Chikara, Tamaoki, Tatsuya, Akinaga, Shiro |
| Zdroj: |
Blood; September 2000, Vol. 96 Issue: 6 p2284-2291, 8p |
| Abstrakt: |
Chronic myelogenous leukemia (CML) is a clonal disorder of a pluripotent hematopoietic stem cells characterized by a chimericbcr-abl gene giving rise to a p210Bcr-Ablprotein 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 p27Kip1protein 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. |
| Databáze: |
Supplemental Index |
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