PUBLICATION
Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth
- Authors
- Lyu, J., Yang, E.J., Head, S.A., Ai, N., Zhang, B., Wu, C., Li, R.J., Liu, Y., Yang, C., Dang, Y., Kwon, H.J., Ge, W., Liu, J.O., Shim, J.S.
- ID
- ZDB-PUB-170920-11
- Date
- 2017
- Source
- Cancer letters 409: 91-103 (Journal)
- Registered Authors
- Ge, Wei
- Keywords
- Cholesterol trafficking, angiogenesis, cepharanthine, lysosome, tumor
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology
- Animals
- Animals, Genetically Modified
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Benzylisoquinolines/administration & dosage
- Benzylisoquinolines/pharmacology*
- Cell Growth Processes/drug effects
- Cholesterol/metabolism*
- Cisplatin/administration & dosage
- Cisplatin/pharmacology
- Drug Synergism
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Lysosomes/drug effects
- Lysosomes/metabolism
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Neoplasms/blood supply*
- Neoplasms/drug therapy*
- Neoplasms/metabolism
- Neoplasms/pathology
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Tumor Microenvironment/drug effects
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 28923401 Full text @ Cancer Lett.
Citation
Lyu, J., Yang, E.J., Head, S.A., Ai, N., Zhang, B., Wu, C., Li, R.J., Liu, Y., Yang, C., Dang, Y., Kwon, H.J., Ge, W., Liu, J.O., Shim, J.S. (2017) Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth. Cancer letters. 409:91-103.
Abstract
Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping