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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.