title: Novel complex of copper and a salicylaldehyde pyrazole hydrazone derivative induces apoptosis through up-regulating integrin beta 4 in vascular endothelial cells.
abstract: To determine apoptosis modulators of human umbilical vein endothelial cells (HUVECs), we prepared 9 novel complexes of copper (Cu) and salicylaldehyde pyrazole hydrazone (SPH) derivatives (Cu-SPHs). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that all of the SPHs and Cu-SPHs effectively inhibited cell growth. Six of the 9 Cu-SPHs induced apoptosis in HUVECs. Among the 9 Cu-SPHs, the complex of Cu and (E)-N'-(2-hydroxybenzylidene)-1-benzyl-3-phenyl-1H-pyrazole-5-carbohydrazide, named Cu-15, was one of the most effective apoptosis inducers and inhibited angiogenesis on Matrigel and HUVEC migration in vitro. We further studied the mechanism of Cu-15 action and found that the protein level of integrin beta 4 increased with 10 microM Cu-15 treatment for 12 or 24 h. Knockdown of integrin beta 4 by RNA interference significantly inhibited apoptosis induced by Cu-15 in HUVECs. Thus, high level of integrin beta 4 could promote apoptosis induced by Cu-15. Cu-15 might be a useful tool for further investigating the functions of integrin beta 4 in regulating angiogenesis and HUVEC apoptosis.
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Baoxiang
authors.initials: B
authors.lastname: Zhao
authors.forename: Shangli
authors.initials: S
authors.lastname: Zhang
authors.forename: Junying
authors.initials: J
authors.lastname: Miao
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D017209:Apoptosis; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry / Q000627:therapeutic use*; D011720:Pyrazoles / Q000737:chemistry*; D034741:RNA, Small Interfering; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C545878:(N'-(2-hydroxybenzylidene)-1-benzyl-3-phenyl-1H-pyrazole-5-carbohydrazide)copper(II); D000447:Aldehydes; D006835:Hydrazones; D039663:Integrin beta4; D009942:Organometallic Compounds; D011720:Pyrazoles; D034741:RNA, Small Interfering; C013243:salicylaldehyde; C031280:pyrazole; D003300:Copper