1. Alkaloid derivative ION-31a inhibits breast cancer metastasis and angiogenesis by targeting HSP90α.
- Author
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Ni TW, Duan XC, Wang M, Jia MQ, Chen Y, Yu Y, Qin N, and Duan HQ
- Subjects
- Alkaloids chemical synthesis, Alkaloids chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, HSP90 Heat-Shock Proteins metabolism, Humans, Molecular Structure, Norisoprenoids chemical synthesis, Norisoprenoids chemistry, Structure-Activity Relationship, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Alkaloids pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, HSP90 Heat-Shock Proteins antagonists & inhibitors, Norisoprenoids pharmacology
- Abstract
Breast cancer has become the number one killer of women. In our previous study, an active compound, ION-31a, with potential anti-metastasis activity against breast cancer was identified through the synthesis of ionone alkaloid derivatives. In the present study, we aimed to identify the therapeutic target of ION-31a. We used a fluorescence tag labeled probe, molecular docking simulation, and surface plasmon resonance (SPR) analysis to identify the target of ION-31a. The main target of ION-31a was identified as heat shock protein 90 (HSP90). Thus, ION-31a is a novel HSP90 inhibiter that could suppress the metastasis of breast cancer and angiogenesis significantly in vitro and in vivo. ION-31a acts via inhibiting the HSP90/hypoxia inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and downregulating downstream signal pathways, including protein kinase B (AKT)/mammalian target of rapamycin (mTOR), AKT2/protein kinase C epsilon (PKCζ), extracellular regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and mitogen-activated protein kinase 14 (p38MAPK) pathways. ION-31a affects multiple effectors implicated in tumor metastasis and has the potential to be developed as an anti-metastatic agent to treat patients with breast cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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