Tanshinone I inhibits tumor angiogenesis by reducing STAT3 phosphorylation at TYR705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells

// Yan Wang 1, 2 , Jia-Xin Li 1 , Ying-Qing Wang 1 , Ze-Hong Miao 1 1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica , Chinese Academy of Sciences, Shanghai 201203, China 2 College of Pharmacy, Nanchang University, Nanchang 330006, China Correspondence to: Ze-Hong Miao, e-mail: zhmiao@simm.ac.cn Ying-Qing Wang, e-mail: yqwang@simm.ac.cn Keywords: tanshinone I, angiogenesis, Stat3, HIF-1α, VEGF Received: February 15, 2015      Accepted: March 23, 2015      Published: April 10, 2015 ABSTRACT Tanshinone I (Tanshinone-1), a major active principle of Salvia miltiorrhiza (Danshen), has been shown to overcome tumor drug resistance and metastasis. Here we report that tanshinone-1 inhibits angiogenesis. Tanshinone-1 inhibited proliferation, migration and tube formation of vascular endothelial cells, rat aortic ring sprouting and the neovascularization of the chick chorioallantoic membrane in a concentration-dependent manner. In endothelial cells, tanshinone-1 almost completely inhibited phosphorylation of Stat3 at Tyr705 regardless of hypoxia or normoxia but only slightly decreased the hypoxia-induced HIF-1α accumulation. In tumor cells, contrastively, tanshinone-1 could not only make phosphorylation of Stat3 at Tyr705 disappear but also reduce the hypoxia-induced accumulation of HIF-1α to its baseline levels at normoxia. Consequently, VEGF secretion from tumor cells was reduced, which could potentiate the direct inhibition of tanshinone-1 on endothelial cells. Together with its overcoming tumor drug resistance and metastasis, our results reveal unique characteristics of tanshinone-1 and its improved derivatives as promising angiogenesis inhibitors.