Premium
PPemd 26, an anthraquinone derivative, suppresses angiogenesis via inhibiting VEGFR2 signalling
Author(s) -
Huang S W,
Lien J C,
Kuo S C,
Huang T F
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12872
Subject(s) - angiogenesis , matrigel , ex vivo , cancer research , mapk/erk pathway , neovascularization , kinase , in vivo , cd31 , protein kinase b , microbiology and biotechnology , biology , chemistry , pharmacology , phosphorylation
Background and Purpose Angiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF ‐ A and its receptors ( VEGFRs ) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd 26, and explored its anti‐angiogenic mechanisms. Experimental Approach The effects of PPemd 26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models. Key Results PPemd 26 significantly inhibited VEGF ‐ A ‐induced proliferation, migration, invasion and tube formation of HUVECs . PPemd 26 also attenuated VEGF ‐ A ‐induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo . In addition, PPemd 26 inhibited VEGF ‐A‐induced phosphorylation of VEGFR2 and its downstream protein kinases including A kt, focal adhesion kinase, ERK and S rc. Furthermore, systemic administration of PPemd 26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo . Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD 31 and proliferation marker Ki ‐67. Conclusions and Implications This study provides evidence that PPemd 26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd 26 is a potential drug candidate for developing anti‐angiogenic agents for the treatment of cancer and angiogenesis‐related diseases.