RT Journal Article
SR Electronic
T1 The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.218644
DO 10.1124/jpet.114.218644
A1 Beibei Wang
A1 Weiwei Yu
A1 Jiawei Guo
A1 Xingwu Jiang
A1 Weiqiang Lu
A1 Mingyao Liu
A1 Xiufeng Pang
YR 2014
UL http://jpet.aspetjournals.org/content/early/2014/10/28/jpet.114.218644.abstract
AB Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various non-small cell lung cancer cells (NSCLC) with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dose of 40 mg/kg ( i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo anti-angiogenesis property of PAT, which was well-correlated with its tumor growth inhibition in NSCLC. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor (VEGF)-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC. Further study of PAT in anticancer clinical trials may be warranted.