Heat shock protein 90 (Hsp90) is a molecular chaperone protein that stabilizes client oncogenic proteins in breast cancer cells. PU-H71 is a novel Hsp90 inhibitor with an IC50 value of 51nM. The treatment with PU-H71 at a dosage of 1µM resulted in significant cell death in triple-negative breast cancer (TNBC) cell lines MDA-MB-468 (80%), MDA-MB-231 (65%), and HCC-1806 (80%). The inhibition of Hsp90 by PU-H71 (10–1000nM) induced a concentration-dependent inactivation or degradation of tumor driving molecules, including epidermal growth factor receptor, insulin-like growth factor receptor, HER3, and c-Kit. PU-H71 (10–1000nM) also downregulated the proteins related to G2-M progression, such as cyclin-dependent kinase 1 and checkpoint kinase 1. The treatment of MDA-MB-468 cells with 0.25, 0.5, and 1μM PU-H71 for 24 h increased the percentage of cells in G2-M phase to 30%, 44%, and 69%, respectively. PU-H71 at 250–1000nM induced apoptosis in TNBC cells by inactivating and downregulating Bcl-xL and Akt. The treatment of MDA-MB-231 cells with 0.5 and 1μM PU-H71 for 24 h reduced the NF-κB activity by 84% and 90%, respectively. In the MDA-MB-231 xenograft mouse model, PU-H71 (75 mg/kg on an alternate day schedule) completely inhibited tumor growth after 37 days of treatment. In the fast growing HCC-1806 tumors, six doses of PU-H71 (75 mg/kg on an alternate day schedule) over a 12 days resulted in an 87% regression in tumor volume.
作用机制
PU-H71 is a potent inhibitor of Hsp90 both in vitro and in vivo. When Hsp90 is inactivated, many TNBC oncoproteins that form a complex with PU-H71-bound Hsp90 become destabilized and subsequently degraded.
Zelavespib 细胞研究
细胞系
浓度
检测类型
检测时间
活性说明
数据源
H69AR cells
Function assay
96 h
Inhibition of HSP90-mediated antiapoptotic activity in human H69AR cells assessed as induction of cell growth arrest at 10 after 96 hrs by propidium iodide staining-based flow cytometry
17603540
MCF7 cells
Function assay
24 h
Inhibition of Hsp90 in human MCF7 cells assessed as Her2 level after 24 hrs by Western blot, IC50=0.06 μM
18571929
MDA-MB-468 cells
Function assay
Inhibitory activity against Hsp90 in human breast cancer MDA-MB-468 cell line, EC50=0.0102 μM
16392823
MRC5 cells
Cytotoxicity assay
Cytotoxicity against normal lung fibroblast MRC5 cell line, IC50=1 μM
Inhibition of HSP90-mediated antiapoptotic activity in human H69AR cells assessed as induction of cell growth arrest at 10 after 96 hrs by propidium iodide staining-based flow cytometry
17603540
MCF7 cells
Function assay
24 h
Inhibition of Hsp90 in human MCF7 cells assessed as Her2 level after 24 hrs by Western blot, IC50=0.06 μM
18571929
MDA-MB-468 cells
Function assay
Inhibitory activity against Hsp90 in human breast cancer MDA-MB-468 cell line, EC50=0.0102 μM
16392823
MRC5 cells
Cytotoxicity assay
Cytotoxicity against normal lung fibroblast MRC5 cell line, IC50=1 μM
16392823
NCI-H1299 cells
Function assay
12 h
Reduction in oxygen consumption rate in human NCI-H1299 cells incubated for 12 hrs
25383915
NCI-H187 cells
Function assay
24 h
Binding affinity to HSP90 in human NCI-H187 cells after 24 hrs by fluorescence polarization assay
17603540
NCI-H510 cells
Function assay
24 h
Binding affinity to HSP90 in human NCI-H510 cells after 24 hrs by fluorescence polarization assay
17603540
NCI-H526 cells
1 μM
Function assay
24 h
Binding affinity to HSP90 in human NCI-H526 cells at 1 uM after 24 hrs by fluorescence polarization assay
17603540
NCI-H526 cells
Function assay
24 h
Binding affinity to HSP90 in human NCI-H526 cells after 24 hrs by fluorescence polarization assay
17603540
NCI-H69 cells
Function assay
24 h
Binding affinity to HSP90 in human NCI-H69 cells after 24 hrs by fluorescence polarization assay
17603540
NCI-N417 cells
Function assay
24 h
Binding affinity to HSP90 in human NCI-N417 cells after 24 hrs by fluorescence polarization assay
17603540
SKBr3 cells
Growth inhibition assay
Growth inhibition in human breast cancer SKBr3 cell line using SRB, IC50=0.05 μM
16392823
SKBR3 cells
Function assay
24 h
Binding affinity to HSP90 in human SKBR3 cells after 24 hrs by fluorescence polarization assay
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