Suppression of mitochondrial dynamic with artemisinin inhibits VEGF-mediated tumor angiogenesis via auto-paracine mechanisms
Meng-Yu Wu1,2, Giou-TengYiang1,2, Chia-Jung Li1*
1Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231; 2Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien 970, Taiwan; 3Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan
Tumor angiogenesis is an important process involved in the development, progression, tumor growth, and metastasis of cancer. The antiangiogenic strategy knows as metronomic chemotherapy, with frequent and administration of low-dose chemotherapeutic agents to treat solid tumors by antiangiogenic activity and reduce side effects. Here, we examined that the efficacy of artemisinin targeting tumor-associated endothelial cells. This goal of the present study was to investigate potential anti-angiogenic mechanisms of low-doses combined treatment in vitro and in vivo. We now report that artemisinin inhibited tumor cell growth, and conditioned medium from combined treatment breast cancer cells can suppressed the tube formation of human umbilical vein endothelial cells in a paracrine manner and inhibited the proliferation of cancer cells in an autocrine and a paracrine manner. Furthermore, artemisinin inhibit breast solid tumor progression in xenograft models, in association with a reduction in tumor microvessel density. This is the ﬁrst report on the artemisinin increased nuclear accumulation of nuclear factor kappa B and activator protein-1 subunit c-fos, leading to transcriptional inhibition down-regulation of VEGF expression on cancer cells. In parallel, we also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in artemisinin administration. These findings support the hypothesis that the anti-tumor activity of artemisinin on cancer and endothelial cells are possibly mediated by targeting the auto-paracrine effects of VEGF to suppress tumor biogenesis, angiogenesis and migration between cancer cells and endothelial cells.