Inhibitory effect of DA-125, a new anthracyclin analog antitumor agent, on the invasion of human fibrosarcoma cells by down-regulating the matrix metalloproteinases.
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.
Park
Hyen Joo
HJ
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Ku, Seoul 120-750, Republic of Korea.
Chung
Hwa-Jin
HJ
Min
Hye-Young
HY
Park
Eun-Jung
EJ
Hong
Ji-Young
JY
Kim
Won Bae
WB
Kim
Soon Hoe
SH
Lee
Sang Kook
SK
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
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