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

• Published in: Cancer chemotherapy and pharmacology 2012-06, Vol.69 (6), p.1633-1640
• Main Authors: Liu, Ziwei, Yuan, Qianying, Zhang, Xuenong, Xiong, Chaomei, Xue, Pingping, Ruan, Jinlan
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cancer Research; 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; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; 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
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1873-3

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.