Anti-metastatic and anti-angiogenic activities of a new matrix metalloproteinase inhibitor, TN-6b.
We investigated the anti-metastatic and anti-angiogenic effects of TN-6b, a new broad-spectrum inhibitor of matrix metalloproteinases (MMPs), against Lewis lung carcinoma (LLC) and hepatic sinusoidal endothelial (HSE) cells. TN-6b potently inhibited the activities of MMP-2 and -9 secreted by LLC and HSE cells in a zymogram assay. TN-6b, at non-cytotoxic concentrations, caused a marked inhibition of invasion and migration of LLC, and tube-like formation of HSE cells. In contrast, TN-6d, an inactive enantiomer of TN-6b, did not inhibit the invasion and tube-like formation. Daily subcutaneous (s.c.) administration of TN-6b at doses of 30 and 60 mg/kg in mice resulted in a potent inhibition of tumour-induced angiogenesis of B16 melanomas and lymph node metastasis of LLC cells. In conclusion, TN-6b effectively inhibited lymph node metastasis of LLC cells through its anti-invasive and anti-angiogenic properties. These findings suggest that the MMP inhibition correlates well with its anti-angiogenic and anti-metastatic efficacy and TN-6b has the therapeutic potential to inhibit angiogenesis and metastasis in vivo and in vitro.
Lee
S J
SJ
Department of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Japan.
Sakurai
H
H
Oshima
K
K
Kim
S H
SH
Saiki
I
I
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001555:Benzene Derivatives / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008207:Lymphatic Metastasis / Q000517:prevention & control; D061965:Matrix Metalloproteinase Inhibitors; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C476702:TN-6b compound