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Inhibition of angiogenesis and tumor growth by a novel 1,4‐naphthoquinone derivative
Author(s) -
Murota Hiroko,
Shinya Tomohiro,
Nishiuchi Arisa,
Sakanaka Mariko,
Toda Kenichi,
Ogata Tokutaro,
Hayama Noboru,
Kimachi Tetsutaro,
Takahashi Satoru
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21513
Subject(s) - angiogenesis , basic fibroblast growth factor , angiogenesis inhibitor , pharmacology , vascular endothelial growth factor , endothelial stem cell , in vivo , cancer research , fibroblast growth factor , cell growth , chemistry , receptor , in vitro , biology , growth factor , biochemistry , vegf receptors , microbiology and biotechnology
Hit, Lead & Candidate DiscoveryAntiangiogenesis therapy is a promising way for treatment of solid cancers, and many angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) or its receptors have been developed. We explored novel antiangiogenic compounds other than anti‐VEGF drugs by screening our synthetic compound library and found that 6‐thiophen‐3‐yl‐2‐methoxy‐1,4‐naphthoquinone (6‐TMNQ) had potential as a novel angiogenesis inhibitor. This paper describes the effects of 6‐TMNQ on angiogenesis and tumor growth in vitro and in vivo. 6‐TMNQ inhibited serum‐, VEGF‐, and basic fibroblast growth factor (bFGF)‐stimulated proliferation of endothelial cells in a concentration‐dependent manner, but had no effect on the proliferation of fibroblasts. VEGF‐induced activation of VEGF receptor‐2 in endothelial cells was not affected by the compound. 6‐TMNQ markedly abrogated both migration and tube formation of endothelial cells. Orally administered 6‐TMNQ inhibited angiogenesis in response to VEGF or bFGF in mice in a dose‐dependent manner. Furthermore, when tumor‐bearing mice were treated with 6‐TMNQ, increase in tumor size was significantly prevented due to inhibition of angiogenesis in the tumor tissues. These results demonstrate that 6‐TMNQ is an orally available compound that selectively inhibits endothelial cell proliferation and migration, and abrogates angiogenesis, resulting in the prevention of tumor growth. The mechanism of 6‐TMNQ action is different from that of conventional anti‐VEGF drugs.