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AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo
- Source :
- Biochemical Pharmacology. 172:113771
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- The inhibition of angiogenesis is suggested to be an attractive strategy for cancer therapeutics. Heat shock protein 90 (Hsp90) is closely related to tumorigenesis as it regulates the stabilization and activated states of many client proteins that are essential for cell survival and tumor growth. Here, we investigated the mechanism whereby AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and tumor angiogenesis. Based on our results, AT-533 suppressed the tube formation, cell migration, and invasion of human umbilical vein endothelial cells (HUVECs), and was more effective than the Hsp90 inhibitor, 17-AAG. Furthermore, AT-533 inhibited angiogenesis in the aortic ring, Matrigel plug, and chorioallantoic membrane (CAM) models. Mechanically, AT-533 inhibited the activation of VEGFR-2 and the downstream pathways, including Akt/mTOR/p70S6K, Erk1/2 and FAK, in HUVECs, and the viability of breast cancer cells and the HIF-1α/VEGF signaling pathway under hypoxia. In vivo, AT-533 also inhibited tumor growth and angiogenesis by inducing apoptosis and the HIF-1α/VEGF signaling pathway in breast cancer cells. Taken together, our findings indicate that the Hsp90 inhibitor, AT-533, suppresses breast cancer growth and angiogenesis by blocking the HIF-1α/VEGF/VEGFR-2 signaling pathway. AT-533 may thus be a potentially useful drug candidate for breast cancer therapy.
- Subjects :
- Vascular Endothelial Growth Factor A
Indazoles
Cell Survival
Angiogenesis
Mice, Nude
Antineoplastic Agents
Breast Neoplasms
medicine.disease_cause
Biochemistry
Hsp90 inhibitor
Mice
Cell Movement
Cell Line, Tumor
VEGF Signaling Pathway
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
HSP90 Heat-Shock Proteins
Protein kinase B
PI3K/AKT/mTOR pathway
Pharmacology
Tube formation
Molecular Structure
Neovascularization, Pathologic
Chemistry
Cancer
Neoplasms, Experimental
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Vascular Endothelial Growth Factor Receptor-2
Gene Expression Regulation, Neoplastic
Cancer research
Female
Carcinogenesis
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 172
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....ff31c96bd915836e7aa80f94c519c673