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Inhibitory effect of DA-125, a new anthracyclin analog antitumor agent, on the invasion of human fibrosarcoma cells by down-regulating the matrix metalloproteinases.

Abstract
Matrix metalloproteinases (MMPs), zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. In this study, we examined the influence of DA-125, a new anthracyclin analog, on the gene expression of MMPs (MMP-2, MMP-9 and MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases of MMPs and TIMPs mRNA levels were observed in DA-125-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. Gelatin zymography analysis also showed a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with DA-125 compared to controls. In addition, DA-125 inhibited the invasion, motility and cell migration, and colony formation of tumor cells. These data, therefore, provide direct evidence for the role of DA-125 as a potential cancer chemotherapeutic agent, which can markedly inhibit the invasive capacity of malignant cells. Further, to clarify the transcriptional regulatory pathway, we primarily investigated the role of nuclear factor-kappaB (NF-kappaB) in the expression of MMPs by DA-125 in HT1080 cells. Electrophoretic mobility shift assay demonstrated that DA-125 modulates the binding activity of NF-kappaB. Using the luciferase reporter gene assay, a dose-dependent down-regulation of NF-kappaB-mediated luciferase expression was also observed. These results suggest that DA-125 down-regulates MMPs expression in HT1080 cells through the NF-kappaB-mediated pathway.
AuthorsHyen Joo Park, Hwa-Jin Chung, Hye-Young Min, Eun-Jung Park, Ji-Young Hong, Won Bae Kim, Soon Hoe Kim, Sang Kook Lee
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 71 Issue 1-2 Pg. 21-31 (Dec 19 2005) ISSN: 0006-2952 [Print] England
PMID16271263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anthracyclines
  • Antineoplastic Agents
  • DNA Primers
  • NF-kappa B
  • 7-O-(2,6-Dideoxy-2-fluoro-alpha-talopyranosyl)adriamycinone- 14-beta-alaniate hydrochloride
  • Doxorubicin
  • Matrix Metalloproteinases
Topics
  • Anthracyclines (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Base Sequence
  • Cell Line, Tumor
  • DNA Primers
  • Down-Regulation
  • Doxorubicin (analogs & derivatives, pharmacology)
  • Electrophoretic Mobility Shift Assay
  • Fibrosarcoma (enzymology, pathology)
  • Humans
  • Matrix Metalloproteinases (metabolism)
  • NF-kappa B (metabolism, physiology)
  • Neoplasm Invasiveness
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic (physiology)

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