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Int J Biochem Cell Biol. 2013 Aug;45(8):1710-9. doi: 10.1016/j.biocel.2013.04.030. Epub 2013 May 20.

Deoxypodophyllotoxin exerts both anti-angiogenic and vascular disrupting effects.

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1
Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China.

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.

KEYWORDS:

Anti-angiogenesis; Deoxypodophyllotoxin; G2/M arrest; Microtubule; Vascular disrupting effect

PMID:
23702033
DOI:
10.1016/j.biocel.2013.04.030
[Indexed for MEDLINE]
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