title: 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.
authors.affiliation: College of Pharmacy, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Ku, Seoul 120-750, Republic of Korea.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Won Bae
authors.initials: WB
authors.lastname: Kim
authors.forename: Soon Hoe
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D017931:DNA Primers; D016328:NF-kappa B; C090816:7-O-(2,6-Dideoxy-2-fluoro-alpha-talopyranosyl)adriamycinone- 14-beta-alaniate hydrochloride; D004317:Doxorubicin; D020782:Matrix Metalloproteinases