Increase in tissue inhibitor of metalloproteinase-2 (TIMP-2) levels and inhibition of MMP-2 activity in a metastatic breast cancer cell line by an anti-invasive small molecule SR13179.

Abstract

Tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of matrix metalloproteinase-2 (MMP-2), regulates tumor invasion by modulating the activity of MMP-2. In addition, TIMP-2 is involved in the direct regulation of cell growth and angiogenesis, independent of MMP inhibition. Therefore, the development of therapeutic agents that increase TIMP-2 levels may offer a novel and broad approach to anti-neoplastic therapy. We report that a novel small molecule synthetic flavanoid SR13179, which inhibits the invasion of a highly metastatic human breast cancer cell line MCF-10CA1a through Matrigel, significantly increases protein and mRNA levels of TIMP-2 in a time- and dose-dependent manner. SR13179 inhibits the gelatinolytic activity of MMP-2 by >50% but has no effect on MMP-2 protein expression. SR13179 also possesses potent anti-tumor activity in several tumor cell lines regardless of their hormone receptor, p53 or multi-drug resistance status. Given the multifunctional inhibitory activity of TIMP-2 on tumor growth and invasion, the observed increase in TIMP-2 expression by SR13179 may play a central role in the anti-tumor and anti-invasive activity of this novel small molecule. Modulation of TIMP-2 protein expression may be a new molecular target for anti-metastatic adjuvant therapy for breast and other cancers.

• Authors: Nahid S Waleh, Brian J Murphy, Nurulain T Zaveri
• Journal: Cancer letters (Cancer Lett) Vol. 289 Issue 1 Pg. 111-8 (Mar 01 2010) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 19751965 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Flavonoids
• Matrix Metalloproteinase Inhibitors
• SR 13179
• Tissue Inhibitor of Metalloproteinase-2
• Matrix Metalloproteinase 2

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Blotting, Western
• Breast Neoplasms (enzymology)
• Cell Line, Tumor
• Female
• Flavonoids (chemical synthesis, pharmacology)
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Neoplasm Invasiveness
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• Up-Regulation (drug effects)