The Hsp90 inhibitor 17-allylamide-17-demethoxygeldanamycin induces apoptosis and differentiation of Kasumi-1 harboring the Asn822Lys KIT mutation and down-regulates KIT protein level.
Heat shock protein 90 (Hsp90) serves as a chaperone for a number of cell signaling proteins, including many tyrosine and serine/threonine kinases, which are involved in proliferation and/or survival. The benzoquinone ansamycin geldanamycin has been shown to bind to Hsp90 and to specifically inhibit this chaperone's function, resulting in client protein destabilization. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a chemical derivative of geldanamycin. KIT is the receptor for stem cell factor (SCF) and required for normal hematopoiesis. Mutations in c-Kit result in ligand-independent tyrosine kinase activity and uncontrolled cell proliferation. Kasumi-1 is t(8;21) acute myeloid leukemia (AML) cell line harboring mutated KIT with Asn822Lys substitution. Our present studies demonstrate that 17-AAG inhibits Kasumi-1 cells proliferation and exerts apoptosis- and differentiation-inducing effects in a dose- and time-dependent manner. The growth-inhibitory IC50 value for 17-AAG treatment is 0.62mumol/L. Characteristic apoptotic features were confirmed by morphology, internucleosomal DNA fragmentation, and annexin V staining. 17-AAG also causes the G0/G1 block of Kasumi-1 cells. Significantly, 17-AAG-induced apoptosis of Kasumi-1 cells is associated with a decline in KIT protein level. Our findings strongly suggest that 17-AAG might be an effective therapeutic agent targeting AML cells harboring mutated KIT.
Yu
Wenjuan
W
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China.
Rao
Qing
Q
Wang
Min
M
Tian
Zheng
Z
Lin
Dong
D
Liu
Xiangrong
X
Wang
Jianxiang
J
D017209:Apoptosis / Q000187:drug effects*; D001216:Asparagine / Q000235:genetics; D016227:Benzoquinones / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008239:Lysine / Q000235:genetics; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; C112765:tanespimycin; D001216:Asparagine; D019009:Proto-Oncogene Proteins c-kit; D008239:Lysine