title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation of Hubei Province, College of Pharmacy, Huazhong University of Science and Technology, HangKong Road, Wuhan, 430070, Hubei Province, China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Qianying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Xuenong
authors.initials: X
authors.lastname: Zhang
authors.forename: Chaomei
authors.initials: C
authors.lastname: Xiong
authors.forename: Pingping
authors.initials: P
authors.lastname: Xue
authors.forename: Jinlan
authors.initials: J
authors.lastname: Ruan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish
chemical_list: C574037:2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)pyran-4-one; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011753:Pyrones; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases