title: Deoxypodophyllotoxin exerts both anti-angiogenic and vascular disrupting effects.
abstract: A functioning vascular supply is essential for solid tumor growth and metastases, which means that blood vessels are an ideal target for antitumor drug discovery. Targeting tumor vasculature involves two main approaches, anti-angiogenesis and vascular disruption. The anti-angiogenic and vascular disrupting activities of deoxypodophyllotoxin (DPT), a natural microtubule destabilizer, were examined with several in vitro, ex vivo and/or in vivo models. First, we demonstrated that DPT significantly inhibits the proliferation, migration and tube formation of endothelial cells and inhibits angiogenesis in rat aortic ring and chick chorioallantoic membrane assays. In further studies, DPT induced cytoskeleton reorganization in endothelial cells, which likely contributed to the anti-angiogenic effect at non-cytotoxic concentrations. DPT treatment at higher concentrations for longer time induced the cell cycle arrest, which may contributes to its anti-proliferation effect and anti-angiogenic activity. And DPT dramatically inducted the expression of cyclin B1 and p21 (WAF1/CIP1). Meanwhile, DPT disrupted capillary-like networks in vitro and newly formed vessels from rat aortic rings. Endothelial cell contraction associated with an increase in F-actin via the Rho/Rho kinase pathway likely contributed to the vascular disrupting activity. Taken together, our results provided the initial evidence that DPT exerts potent anti-angiogenic and vascular disrupting effects. This study also provides important insight into the mechanism of action of promising new anticancer drugs with both anti-angiogenic and vascular disrupting activities.
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Meijuan
authors.initials: M
authors.lastname: Wu
authors.forename: Jingshan
authors.initials: J
authors.lastname: Miao
authors.forename: Huaqin
authors.initials: H
authors.lastname: Duan
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.forename: Yurong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xueji
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhu
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000577:Amides / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004365:Drugs, Chinese Herbal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D020533:Angiogenesis Inhibitors; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004365:Drugs, Chinese Herbal; D011725:Pyridines; C108830:Y 27632; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin; D017239:Paclitaxel
keywords: Anti-angiogenesis; Deoxypodophyllotoxin; G2/M arrest; Microtubule; Vascular disrupting effect