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Dorsomorphin Induces Cancer Cell Apoptosis and Sensitizes Cancer Cells to HSP90 and Proteasome Inhibitors by Reducing Nuclear Heat Shock Factor 1 Levels

Dorsomorphin Induces Cancer Cell Apoptosis and Sensitizes Cancer Cells to HSP90 and Proteasome Inhibitors by Reducing Nuclear Heat Shock Factor 1 Levels

Na Li, Ting Wang, Zongmeng Li, Xiaoli Ye, Bo Deng, Shu Zhuo, Pengle Yao, Mengmei Yang, Hong Mei, Xiaofang Chen, Tengfei Zhu, Shiting Chen, Hui Wang, Jiming Wang, Yingying Le

Cancer Biol Med. 2019 May;16(2):220-233.

PMID: 31516744

Abstract:

Objective:
Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.
Methods:
The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.
Results:
Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.
Conclusions:
Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP866405643	Dorsomorphin		866405-64-3	Price

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