Fisetin Inhibits Matrix Metalloproteinases and Reduces Tumor Cell Invasiveness and Endothelial Cell Tube Formation

Abstract

Matrix metalloproteinases (MMPs) play an important role in tissue remodeling during normal physiological situations and pathological implications such as tumor invasion and metastasis. MMP inhibitors were screened from extracts of medicinal herbs by an enzymatic assay using the MMP-14 catalytic domain. Among samples tested, a methanol extract of the root of Dalbergia odorifera T. CHEN (Leguminosae) showed the strongest inhibitory activity. The inhibitory component was purified through fractionation methods and identified as fisetin, abundant in many fruits and vegetables. In addition to inhibition of MMP-14, fisetin inhibits MMP-1, MMP-3, MMP-7, and MMP-9, more efficiently than a naturally occurring MMP inhibitor tetracycline. Fisetin dose-dependently inhibits proliferation of fibrosarcoma HT-1080 cells and human umbilical vascular endothelial cells (HUVECs), MMP-14-mediated activation of proMMP-2 in HT-1080 cells, invasiveness of HT-1080 cells, and in vitro tube formation of HUVECs. Therefore, fisetin could be valuable as a chemopreventive agent against cancer and a lead compound for development of therapeutic MMP inhibitors.

ACKNOWLEDGMENTS

This work was supported by grants from Studies on Ubiquitome Functions (2005–2001143 to Seung-Taek Lee), the Mid-Career Researcher Program (2010–0026103 to Seung-Taek Lee), and the National Core Research Center Program (2010–006123 to Hwa-Jung Kim) of the National Research Foundation, Ministry of Education, Science, and Technology, Republic of Korea and by the National R&D Program for Cancer Control (9920180 and 1120110 to Seung-Taek Lee) from Ministry of Health and Welfare, Republic of Korea. Jun Hyoung Park and Yoon-Jung Jang were predoctoral trainees of the Brain Korea 21 program from Ministry of Education, Science, and Technology, Republic of Korea, and Jun Hyoung Park was a post-doctoral trainee of the 2011 Yonsei University Research Fund. Jun Hyoung Park and Yoon-Jung Jang contributed equally to this article.