2. Academic Validation
  3. AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo

AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo

  • Biochem Pharmacol. 2020 Feb;172:113771. doi: 10.1016/j.bcp.2019.113771.
Peng-Chao Zhang 1,  Xiao Liu 2,  Man-Mei Li 3,  Yan-Yan Ma 1,  Hong-Tao Sun 4,  Xu-Yan Tian 2,  Yan Wang 1,  Min Liu 1,  Liang-Shun Fu 1,  Yi-Fei Wang 1,  Hong-Yuan Chen 5,  Zhong Liu 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 2 Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou 510632, China.
  • 3 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 4 Department of Orthopedics, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
  • 5 Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou 510632, China. Electronic address: hychen@gdpu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: tliuzh@jnu.edu.cn.
PMID: 31863779 DOI: 10.1016/j.bcp.2019.113771
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.

Keywords

Angiogenesis; HIF-1α; Hsp90 inhibitor; VEGF; VEGFR-2.

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