Potassium Antimony Tartrate Suppresses The Growth And Angiogenesis Of Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer mortality in the worldwild, and approximately 85% of all lung cancer cases are non-small cell lung cancer. Cancer-associated angiogenesis is essential for tumor growth and progression. Currently, the angiogenesis inhibitor approved for use in non-small cell lung cancer (NSCLC) patients is bevacizumab. However, there are several limitations to the clinical utility of bevacizumab, such as the toxicities, substantial cost and modest survival rates. Thus, it is urgent to develop less toxic, low cost, and more effective therapies for NSCLC. Potassium antimonyl tartrate (PAT), a clinical antiparasitic agent, has been shown to exert cytotoxicity towards acute promyelocytic leukaemia cells in vitro. However, whether PAT could modulate tumor angiogenesis and tumor growth in NSCLC have not been reported yet. By the screening the small molecule liabrary of Food and Drug Administration (FDA) approved drugs (1280), we identified PAT as an antiangiogenic agent. In vivo, xenografts of NSCLC using A549 lung cancer cell and patient tumor sample, we found that PAT at dose of 40 mg/kg (i.p., once a day) led to remarkably decrease in the volume and weight of solid tumors (p<0.001). Additionally PAT dramatically enhanced the antitumor efficacy of chemotherapy drug cisplatin in such model systems. CD31 and Ki-67 immunohistochemistry futher revealed that tumor microvessel density and cell proliferation was suppressed by PAT. To figure out the mechanism of PAT’s action, we tested the cytotoxicity of PAT in vivo. Unexpectedly, we found that a series of NSCLC cells, including A549 cells, are little sensitive to the treatment, but endothelials cells are notably sensitive to the treatment. Furthermore, PAT exhibited specific, potent, and dose-dependent inhibition of angiogenic endothelial cell proliferation, migration, and tube formation in response to both VEGF and bFGF stimulation. Besides, PAT effectively inhibited VEGF-triggered neovascularization in Matrige plugs assay in vivo. These results indicated that the role of PAT in inhibition of the growth and angiogenesis of NSCLC mainly by controling the density of tumor blood vessels in tumor bearing mice. Further mechanism study showed that PAT decreased the activition of receptpr tyrosine kinases (RTKs) expressing on the surface of endothelia cells and further blocked activition of its downstream Src kinase and focal adhesion kinase (FAK) in concentration-dependent manner, but PAT had little effect on AKT and ERK activity. Taken together, our results firstly demonstrated that PAT potently and selectively suppresses tumor-associated angiogenesis and tumor growth NSCLC.