HSP90 (heat shock protein 90) is a cellular ubiquitous molecular chaperone responsible for promoting the conformational mutation and stabilization of several client oncoproteins, including Met, B-Raf, p53, Akt, and Kit, function of which is required by tumor cells to maintain appropriate client protein expression necessary for proliferation and survival. 17-AAG is a geldanamycin-derived HSP90 inhibitor with 100-fold higher binding affinity for Hsp90 derived from tumour cells (IC50=6nM, measured by competitive binding assays using a biotinylated GM probe) than normal cells, which may due to the high ATPase activity of tumour Hsp90 by co-chaperones[1]. Exposure to 5μM 17-AAG reduced Bcr-Abl protein levels in HL-60/Bcr-Abl and K562 cells, and also down-regulated the levels of c-Raf in Bcr-Abl-positive cells and the control HL-60/neo cells. Induced cell apoptosis of HL-60/neo, HL-60/Bcr-Abl and K562 cells can be observed after exposure to 5μM 17-AAG for 24-72h[2]. Intraperitoneal injection with 17-AAG at different doses ranging in 5-40mg/kg every other day for three weeks prolonged the survival of mice injected with TGB lymphoma cells. Administration of 40mg/kg 17-AAG effectively impaired the self-renewal of the lymphoma CSCs in vivo[3].
作用机制
1. 17-AAG is a geldanamycin-derived HSP90 inhibitor which can bind to the N-terminal ATP/ADP-binding domain of Hsp90. 2. As tumour cells gradually accumulate mutant and over expressed signalling proteins, this makes HSP90 become engaged in active chaperoning and stabilization of oncoproteins. This will make HSP90 adopt a high affinity form induced by bound co-chaperone proteins and make HSP90 possess higher activity in tumour cells. This can explain why 17-AAG showed higher binding affinity for Hsp90 derived from tumour cells[1].
Tanespimycin/坦螺旋霉素 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse embryonic fibroblasts (MEFs)
0.5 µM
20 hours
To study the effect of Hsp90 inhibition on P23H opsin aggregation, results showed that 17-AAG reduced P23H protein aggregation in an HSF-1-dependent mechanism.
Hum Mol Genet. 2014 Apr 15;23(8):2164-75
SK-N-SH neuroblastoma cells
1 µM
24 hours
To investigate the effect of Hsp90 inhibition on the R135L opsin mutant, results showed that 17-AAG reduced intracellular accumulation of R135L and restored normal opsin localization.
Hum Mol Genet. 2014 Apr 15;23(8):2164-75
DU145 human prostate cancer cells
230 nM
72 h
To evaluate the growth inhibitory effect of SMA-tanespimycin micelles on DU145 human prostate cancer cells, results showed an IC50 of 230 nM.
Int J Pharm. 2011 Nov 25;420(1):111-7.
HeLa cells
500 nM
18 h
To study the effect of 17-AAG on Hsp90 conformation, results showed that 17-AAG induced conformational changes in Hsp90, including the closing of the ATP-binding pocket and increased interaction between the NTD and MD.
Cell Chem Biol. 2016 Jun 23;23(6):716-26.
HCC827
0.25 µM
72 h
To observe the effect of HSP90 inhibitor 17AAG on HCC827 cells, results showed that p53 remained constant in 3D conditions but was activated in 2D conditions.
Mol Oncol. 2018 Aug;12(8):1264-1285.
A549
0.25 µM
72 h
To observe the effect of HSP90 inhibitor 17AAG on A549 cells, results showed that HSP60 was significantly upregulated in 3D conditions.
Mol Oncol. 2018 Aug;12(8):1264-1285.
H441
0.25 µM
72 h
To observe the effect of HSP90 inhibitor 17AAG on H441 cells, results showed that p53 was activated in 3D conditions but remained unchanged in 2D conditions.
Mol Oncol. 2018 Aug;12(8):1264-1285.
Leishmania mexicana promastigotes
2 μM, 10 μM, 25 μM
2 h
To investigate the effects of Hsp90 inhibition on nascent protein synthesis in Leishmania mexicana. The results showed that 25 μM tanespimycin significantly decreased nascent protein synthesis, indicating that Hsp90 inhibition significantly affects protein translation.
mSystems. 2021 May 11;6(3):e00089-21.
Leishmania mexicana promastigotes
50 μM
1 h, 4 h
To assess the temporal effect of tanespimycin treatment on global protein synthesis in Leishmania mexicana. The results showed that 4 h of Hsp90 inhibition significantly decreased global nascent protein synthesis, indicating that severe Hsp90 inhibition affects protein translation.
mSystems. 2021 May 11;6(3):e00089-21.
Z138 cells
0.5 and 1.0 µM
24 h
To evaluate the effect of Tanespimycin on Z138 cells, results showed that Tanespimycin significantly inhibited the expression of MYC and CDK9 and induced cell apoptosis.
Exp Hematol Oncol. 2024 Feb 7;13(1):14.
HT29 colon adenocarcinoma cells
62.5 nM
8 h
To investigate changes in protein complexes following HSP90 inhibition, results showed limited changes in protein complex distribution after HSP90 inhibition.
Mol Cell Proteomics. 2023 Feb;22(2):100485.
Tanespimycin/坦螺旋霉素 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Subcutaneous DU145 human prostate cancer tumor xenografts
Tail vein injection
10 mg/kg
Single dose, lasting 23 days
To evaluate the anti-cancer efficacy of SMA-tanespimycin micelles in nude mice bearing subcutaneous DU145 human prostate cancer tumor xenografts, results showed significant tumor growth inhibition.
搜索
