MART-10, the new brand of 1α,25(OH)₂D₃ analog, is a potent anti-angiogenic agent in vivo and in vitro

Background Angiogenesis is the hall marker for cancer growth and metastasis. Thus, anti-angiogenesis emerges as a new way to treat cancer. 1α,25(OH)₂D₃ is recently getting popular due to the non-mineral functions, which have been applied fore cancer treatment. The newly-synthesized 1α,25(OH)₂D₃ analog, MART-10, has been proved to be much more potent than 1α,25(OH)₂D₃ regarding inhibiting cancer cells growth and metastasis without inducing hypercalcemia in vivo. In this study, we aimed to investigate the effect of MART-10 and 1α,25(OH)₂D₃ on angiogenesis in vitro and in vivo. Methods and results MART-10 and 1α,25(OH)₂D₃ were able to repress VEGFA-induced human umbilical vein endothelial cells (HUVECs) migration, invasion and tube formation, but not proliferation, with MART-10 much more potent than 1α,25(OH)₂D₃. The Chick Chorioallantoic Membrane (CAM) assay and matrigeal angiogenesis assay further confirmed the in vivo more potent anti-angiogenesis effect of MART-10. MART-10 inhibited the VEGFA-induced HUVECs angiogenesis process through downregulation of Akt and Erk 1/2 phosphorylation. The VEGFA-VEGFR2 (VEGF receptor 2) axis is the main signal transducing pathway to stimulate angiogenesis. A positive autocrine manner was found for the first time in HUVECs as treated by VEGFA, which induced VEGFA expression and secretion, and VEGFR2 expression. MART-10 and 1α,25(OH)₂D₃ were demonstrated to be able to repress this positive autocrine manner, thus inhibiting angiogenesis. Conclusions MART-10 and 1α,25(OH)₂D₃ both are effective anti-angiogenesis agents. Given MART-10 is much more potent than 1α,25(OH)₂D₃ and active in vivo without obvious side effect, MART-10 should be deemed as a promising anti-cancer agent.