RY10-4, a novel anti-tumor compound, exhibited its anti-angiogenesis activity by down-regulation of the HIF-1α and inhibition phosphorylation of AKT and mTOR
- Authors
- Liu, Z., Yuan, Q., Zhang, X., Xiong, C., Xue, P., and Ruan, J.
- ID
- ZDB-PUB-120510-17
- Date
- 2012
- Source
- Cancer Chemotherapy and Pharmacology 69(6): 1633-1640 (Journal)
- Registered Authors
- Keywords
- RY10-4, anti-angiogenesis, VEGF, HIF-1α, AKT, mTOR
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Antineoplastic Agents/pharmacology*
- Cell Hypoxia
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Down-Regulation
- Female
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors*
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Phosphorylation
- Proto-Oncogene Proteins c-akt/antagonists & inhibitors*
- Proto-Oncogene Proteins c-akt/metabolism
- Pyrones/pharmacology*
- TOR Serine-Threonine Kinases/antagonists & inhibitors*
- TOR Serine-Threonine Kinases/metabolism
- Zebrafish
- PubMed
- 22565593 Full text @ Cancer Chemother. Pharmacol.
Purpose
To assess the anti-angiogenesis potential and mechanism of RY10-4, a derivative of protoapigenone, which was verified the broad-spectrum anti-tumor activities by previous study.
Methods
RY10-4 and RY10-3 were synthesized according to the procedure described. Breast cancer cells MCF-7 and MDA-MB-231 that got the best performance in the previous anti-tumor activity screening were selected for further anti-cancer mechanism research. Firstly, cells proliferation assay of RY10-4 and RY10-3 was used to demonstrate the fact that the 4-hydroxy-2,5-cyclohexadien-1-one system would be the efficient pharmacophore of RY10-4. Then, a series of assays such as human umbilical vein endothelial cells (HUVECs) proliferation assay, HUVECs migration, tube network formation and morphological observations of zebrafish were applied to confirm its anti-angiogenesis activity. Upon RY10-4 treatment, the HIF-1α and VEGF were analyzed by western blot in normoxic and hypoxic conditions, meanwhile the PI3K-AKT-mTOR pathway-related protein such as AKT, p-AKT, mTOR and p-mTOR was also analyzed.
Results
In the MCF-7, MDA-MB-231 and HUVECs proliferation assay, RY10-4 that has 4-hydroxy-2,5-cyclohexadien-1-one system showed distinct advantage compared with RY10-3. Tests had verified the anti-angiogenesis capability of RY10-4. Down-regulation of the HIF-1α and inhibition phosphorylation levels of AKT and mTOR were found to be the pathway that RY10-4 exerts its functions on anti-angiogenesis.
Conclusions
The structure of 4-hydroxy-2,5-cyclohexadien-1-one should be the effective pharmacophore of RY10-4. RY10-4 got fine performance in anti-tumor and anti-angiogenesis assay, and thus, the quinol compound will be the new hot-spot for further anti-tumor agency development.