Inhibitory effects of a benz[f]indole-4,9-dione analog on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells.

Abstract

In our previous study, a synthetic benz[f]indole-4,9-dione analog, 2-amino-3-ethoxycarbonyl-N-methylbenz[f]indole-4,9-dione (SME-6), exhibited a potential anti-tumor activity. We, in this study, further explored the anti-metastatic and anti-invasive effect of SME-6 by determining the regulation of matrix metalloproteinases (MMPs). MMPs, zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. On this line, we examined the influence of SME-6 on the expressions of MMP-2, -9, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1, -2), and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent suppressions of MMPs and TIMP-2 mRNA levels were observed in SME-6-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. TIMP-1 mRNA level, however, was induced in a dose-dependent manner. Gelatin zymographic analysis also exhibited a significant down-regulation of MMP-2 and -9 expression in HT1080 cells treated with SME-6 compared to controls. Furthermore, SME-6 inhibited the invasion, motility, and migration of tumor cells. Taken together, these data provide a possible role of SME-6 as a potential antitumor agent with the markedly inhibition of the metastatic and invasive capacity of malignant cells.

• Authors: Hyen Joo Park, Hyun-Jung Lee, Hye-Young Min, Hwa-Jin Chung, Myung Eun Suh, Hye-Young Park-Choo, Choonmi Kim, Hwa Jung Kim, Eun-Kyung Seo, Sang Kook Lee
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 527 Issue 1-3 Pg. 31-6 (Dec 19 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16309669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-amino-3-ethoxycarbonyl-N-methylbenz(f)indole-4,9-dione
• Imidazoles
• Matrix Metalloproteinase Inhibitors
• Naphthoquinones
• RNA, Messenger
• Tissue Inhibitor of Metalloproteinase-1
• Tissue Inhibitor of Metalloproteinase-2
• Collagenases
• Matrix Metalloproteinases
• Matrix Metalloproteinases, Membrane-Associated
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Cell Line, Tumor
• Cell Movement (drug effects)
• Collagenases (genetics, metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects, genetics)
• Fibrosarcoma (genetics, metabolism, pathology)
• Humans
• Imidazoles (chemistry, pharmacology)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (genetics, metabolism)
• Matrix Metalloproteinases, Membrane-Associated
• Naphthoquinones (chemistry, pharmacology)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Time Factors
• Tissue Inhibitor of Metalloproteinase-1 (antagonists & inhibitors, genetics, metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (antagonists & inhibitors, genetics, metabolism)