A novel polyacetylene significantly inhibits angiogenesis and promotes apoptosis in human endothelial cells through activation of the CDK inhibitors and caspase-7.
A novel bioactive polyacetylene compound, 1,2-dihydroxy-5(E)-tridecene-7,9,11-triyne (compound 1), was identified from the Bidens pilosa extract using an ex vivo primary human umbilical vein endothelium cell (HUVEC) bioassay-guided fractionation protocol. Our results demonstrate that compound 1 (at 2.5 microg/mL) possessed significant anti-angiogenic effects, as manifested by an inhibition of HUVEC proliferation, migration, and the formation of tube-like structures in collagen gel. Moreover, compound 1 induced HUVECs to undergo cell death in a concentration- and time-dependent manner. The mechanisms underlying these pharmacological effects include reduced expression of cell cycle mediators such as CDK4, cyclins D1 and A, retinoblastoma (Rb) and vascular endothelial growth factor receptor 1 (VEGFR-1), and promotion of caspase-mediated activation of CDK inhibitors p21(Cip1) and p27(Kip). Moreover, apoptotic induction in HUVECs mediated by compound 1 was found to be in part through overexpression of FasL protein, down-regulation of anti-apoptotic Bcl-2, and activation of caspase-7 and poly(ADP-ribose) polymerase. This study demonstrates the potent anti-angiogenic and apoptotic activities of compound 1, suggesting that phytocompounds such as polyacetylenes deserve more attention regarding their potential as candidates for anti-angiogenic therapeutics.
Wu
Li-Wha
LW
Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Chiang
Yi-Ming
YM
Chuang
Hsiao-Ching
HC
Lo
Chiu-Ping
CP
Yang
Kai-Ying
KY
Wang
Sheng-Yang
SY
Shyur
Lie-Fen
LF
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D031176:Bidens; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D053279:Polyynes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010936:Plant Extracts; D053279:Polyynes; D053179:Caspase 7