Capsaicin Inhibits in Vitro and in Vivo Angiogenesis
Jeong-Ki Min1, Kyu-Yeon Han4, Eok-Cheon Kim1, Young-Myeong Kim2, Sae-Won Lee5, Ok-Hee Kim3, Kyu-Won Kim5, Yong Song Gho4 and Young-Guen Kwon1
1 Department of Biochemistry, College of Natural Sciences and
2 Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-Do;
3 National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul;
4 Department of Oncology, Graduate School of East-West Medical Science, Kyung Hee University, Yong In; and
5 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a natural product of Capsicum species, is known to induce excitation of nociceptive terminals involved in pain perception. Recent studies have also shown that capsaicin not only has chemopreventive properties against certain carcinogens and mutagens but also exerts anticancer activity.
Here, we demonstrated the antiangiogenic activity of capsaicin using in vitro and in vivo assay systems. In vitro, capsaicin inhibited vascular endothelial growth factor (VEGF) -induced proliferation, DNA synthesis, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells.
Capsaicin inhibited both VEGF-induced vessel sprouting in rat aortic ring assay and VEGF-induced vessel formation in the mouse Matrigel plug assay. Moreover, capsaicin was able to suppress tumor-induced angiogenesis in chick chorioallantoic membrane assay. Capsaicin caused G1 arrest in endothelial cells.
This effect correlated with the down-regulation of the expression of cyclin D1 that led to inhibition of cyclin-dependent kinase 4-mediated phosphorylation of retinoblastoma protein. Signaling experiments show that capsaicin inhibits VEGF-induced p38 mitogen-activated protein kinase, p125FAK, and AKT activation, but its molecular target is distinct from the VEGF receptor KDR/Flk-1.
Taken together, these results demonstrate that capsaicin is a novel inhibitor of angiogenesis and suggest that it may be valuable to develop pharmaceutical drugs for treatment of angiogenesis-dependent human diseases such as tumors.
Cancer Research 64, 644-651, January 15, 2004
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