Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation
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Yurong Wang1, Bin Wang1, Mounia Guerram1, Li Sun1, Wei Shi2, Chongchong Tian1, Xiong Zhu3, Zhenzhou Jiang1,4 and Luyong Zhang1,5
1 Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China
2 Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, P.R. China
3 Medical and Chemical Institute, China Pharmaceutical University, Nanjing, P.R. China
4 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, P.R. China
5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China
Zhenzhou Jiang, email:
Luyong Zhang, email:
Keywords: deoxypodophyllotoxin, tumor vasculature, cytoskeleton remodeling, Rho A, AMP-activated protein kinase
Received: April 09, 2015 Accepted: July 16, 2015 Published: October 06, 2015
Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.
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