Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor

Wenjuan Yu; Jianxiang Wang; Jie Jin; Wenbin Qian; Jiejing Qian; Yizhi Cheng; Lei Wang

doi:10.1016/j.leukres.2011.05.014

Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor

Leuk Res. 2011 Sep;35(9):1212-8. doi: 10.1016/j.leukres.2011.05.014. Epub 2011 May 31.

Authors

Wenjuan Yu¹, Jianxiang Wang, Jie Jin, Wenbin Qian, Jiejing Qian, Yizhi Cheng, Lei Wang

Affiliation

¹ Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China. [email protected]

PMID: 21632108
DOI: 10.1016/j.leukres.2011.05.014

Abstract

KIT mutations may be associated with a poor prognosis in t(8;21) AML. Heat shock protein 90 (Hsp90) is a molecular chaperone frequently used by cancer cells to stabilize mutant oncoproteins. Inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) disrupted downstream signaling pathways of mutant KIT in Kasumi-1 cells. AML1-ETO fusion gene and mutated KIT act as "two-hit" factors in Kasumi-1 cells. Histone deacetylation (HDAC) inhibitors sodium phenylbutyrate (PB) and valproic acid (VPA) block AML1-ETO. Co-treatment with 17-AAG and PB or 17-AAG and VPA resulted in a synergistic effect in Kasumi-1 cells. Our results confirmed that Hsp90 and mutated KIT were valid molecular targets in the therapy of AML.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't
Validation Study

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Benzoquinones / administration & dosage*
Benzoquinones / pharmacology
Cell Line, Tumor
Drug Evaluation, Preclinical
Drug Synergism
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Histone Deacetylase Inhibitors / administration & dosage*
Histone Deacetylase Inhibitors / pharmacology
Humans
Lactams, Macrocyclic / administration & dosage*
Lactams, Macrocyclic / pharmacology
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mutant Proteins / metabolism
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-kit / antagonists & inhibitors
Proto-Oncogene Proteins c-kit / genetics
Proto-Oncogene Proteins c-kit / metabolism
Signal Transduction / drug effects

Substances

Benzoquinones
HSP90 Heat-Shock Proteins
Histone Deacetylase Inhibitors
Lactams, Macrocyclic
Mutant Proteins
Protein Kinase Inhibitors
tanespimycin
Proto-Oncogene Proteins c-kit