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.