Kun-Chun Chiang1, Chi-Chin Sun2, Ming-Huang Chen3, Chi-Ying Huang4, Jun-Te Hsu5, Ta-Sen Yeh5, Li-Wei Chen6, Sheng-Fong Kuo7, Horng-Heng Juang8, Masashi Takano9, Atsushi Kittaka9, Tai C Chen10, Chun-Nan Yeh5, Jong-Hwei S Pang11. 1. General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC. 2. Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC. 3. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. 4. Institute of Clinical Medicine, Institute of Biopharmaceutical Sciences, and Genome Research Center, Yang-Ming University, Taipei, Taiwan, ROC. 5. General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC. 6. Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC. 7. Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC. 8. Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan Taoyuan 333, Taiwan, ROC. 9. Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, 252-5195, Japan. 10. Boston University School of Medicine, M-1022, 715 Albany Street, Boston, MA 02118, USA. 11. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC.
Abstract
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.
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.