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.
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.
Waleh
Nahid S
NS
Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, United States.
Murphy
Brian J
BJ
Zaveri
Nurulain T
NT
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; C548062:SR 13179; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2