MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells - PubMed (original) (raw)
. 2008 Sep;32(9):1382-92.
doi: 10.1016/j.leukres.2008.02.018. Epub 2008 Apr 3.
Affiliations
- PMID: 18394702
- DOI: 10.1016/j.leukres.2008.02.018
Free article
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells
Chie Nishioka et al. Leuk Res. 2008 Sep.
Free article
Abstract
This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene.
Similar articles
- AEE788 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with antiproliferative and proapoptotic effects in acute myeloid leukemia.
Barbarroja N, Torres LA, Rodriguez-Ariza A, Valverde-Estepa A, Lopez-Sanchez LM, Ruiz-Limon P, Perez-Sanchez C, Carretero RM, Velasco F, López-Pedrera C. Barbarroja N, et al. Exp Hematol. 2010 Aug;38(8):641-52. doi: 10.1016/j.exphem.2010.03.017. Epub 2010 Apr 7. Exp Hematol. 2010. PMID: 20380868 - Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling.
Al Shaer L, Walsby E, Gilkes A, Tonks A, Walsh V, Mills K, Burnett A, Rowntree C. Al Shaer L, et al. Br J Haematol. 2008 May;141(4):483-93. doi: 10.1111/j.1365-2141.2008.07053.x. Epub 2008 Mar 27. Br J Haematol. 2008. PMID: 18373709 - Constitutively activated FLT3 phosphorylates BAD partially through pim-1.
Kim KT, Levis M, Small D. Kim KT, et al. Br J Haematol. 2006 Sep;134(5):500-9. doi: 10.1111/j.1365-2141.2006.06225.x. Br J Haematol. 2006. PMID: 16869825 - Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.
Masson K, Rönnstrand L. Masson K, et al. Cell Signal. 2009 Dec;21(12):1717-26. doi: 10.1016/j.cellsig.2009.06.002. Epub 2009 Jun 18. Cell Signal. 2009. PMID: 19540337 Review. - Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia.
Hu X, Chen F. Hu X, et al. Hematology. 2019 Dec;24(1):651-660. doi: 10.1080/16078454.2019.1666219. Hematology. 2019. PMID: 31533545 Review.
Cited by
- Preclinical studies on histone deacetylase inhibitors as therapeutic reagents for endometrial and ovarian cancers.
Singh BN, Zhou H, Li J, Tipton T, Wang B, Shao G, Gilbert EN, Li Q, Jiang SW. Singh BN, et al. Future Oncol. 2011 Dec;7(12):1415-28. doi: 10.2217/fon.11.124. Future Oncol. 2011. PMID: 22112317 Free PMC article. Review. - STAT5 acetylation: Mechanisms and consequences for immunological control and leukemogenesis.
Kosan C, Ginter T, Heinzel T, Krämer OH. Kosan C, et al. JAKSTAT. 2013 Oct 1;2(4):e26102. doi: 10.4161/jkst.26102. Epub 2013 Aug 19. JAKSTAT. 2013. PMID: 24416653 Free PMC article. Review. - New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential.
Li Y, Zhang T, Schwartz SJ, Sun D. Li Y, et al. Drug Resist Updat. 2009 Feb-Apr;12(1-2):17-27. doi: 10.1016/j.drup.2008.12.002. Drug Resist Updat. 2009. PMID: 19179103 Free PMC article. Review. - The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML.
Qiao X, Ma J, Knight T, Su Y, Edwards H, Polin L, Li J, Kushner J, Dzinic SH, White K, Wang J, Lin H, Wang Y, Wang L, Wang G, Taub JW, Ge Y. Qiao X, et al. Blood Cancer J. 2021 Jun 7;11(6):111. doi: 10.1038/s41408-021-00502-7. Blood Cancer J. 2021. PMID: 34099621 Free PMC article. - Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors.
Grant C, Rahman F, Piekarz R, Peer C, Frye R, Robey RW, Gardner ER, Figg WD, Bates SE. Grant C, et al. Expert Rev Anticancer Ther. 2010 Jul;10(7):997-1008. doi: 10.1586/era.10.88. Expert Rev Anticancer Ther. 2010. PMID: 20645688 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous