MMP inhibitor BPHA inhibit the potential of tumor growth and metastasis in human lung cancer cell lin

新开发的基质金属蛋白酶(MMP)抑制剂N-联苯磺酰基苯丙氨酸(BPhA)(Shionogi Co.)有效地抑制基质金属蛋白酶-2、-9和-14，但不抑制基质金属蛋白酶-1、-3或-7和MMI-166(Shionogi Co.)选择性地抑制基质金属蛋白酶-2和-9。采用体外触角侵袭实验检测BPhA和MMI-166对肺癌细胞株MA10和纤维肉瘤细胞株HT-1080体外侵袭能力的抑制作用。明胶酶谱检测显示，HT-1080细胞株具有明胶降解活性。另一方面，MA10细胞株具有明胶溶解活性，但不具有明胶溶解活性，虽然BPhA不能抑制HT-1080和MA10的迁移能力，但它能抑制HT-1080(63%)和MA10(41%)的体外侵袭能力。MMI-166(16微米)对HT-1080(83.4%)和MA10(52.7%)的体外侵袭有抑制作用。此外，我们还通过皮下移植模型和淋巴转移模型验证了MMI-166对MA10细胞生长和淋巴结转移的抑制作用。口服MMI-166(100-300 mg/kg体重)对SCID小鼠无毒副作用。MMI-166 200 mg/kg剂量对皮下肿瘤生长有抑制作用，对淋巴道转移模型小鼠纵隔淋巴道转移有轻微抑制作用。这些结果表明，选择性的基质金属蛋白酶抑制剂不仅能抑制血管生成，还能抑制肿瘤的侵袭。

A newly developed matrix metalloproteinase (MMP) inhibitor, N-biphenyl sulfonylphenylalanine hydroxiamic acid (BPHA)(Shionogi Co.) potently which inhibits MMP-2, -9, and -14 but not MMP-1, -3, or, -7, and MMI-166 (Shionogi Co.) which inhibits MMP-2, and -9 selectively. We examined the inhibition of in vitro invasion potential of lung cancer cell line Ma10 and fibrosarcoma cell line HT-1080 by BPHA and MMI-166 using in vitro haptoinvasion assay. HT-1080 cell line had the gelatinolytic activity of MMP-9 and MMP-2 using gelatin zymography. On the other hand, Ma10 cell line had the gelatinolytic activity of MMP-2 but not MMP-9.Although BPHA did not inhibit the potential of migration for HT-1080 and Ma10, it inhibit the potential of in vitro invasion for HT-1080 (63%) and Ma10 (41%). MMI-166 (16 uM) inhibit the potential of in vitro invasion for HT-1080 (83.4%) and Ma10 (52.7%). Moreover, We exminated the inhibition of tumor growth and lymph nodes metastasis of Ma10 cell line by MMI-166 using subcutaneous implantation model and lymphogenous metastatic model. The oral administration of MMI-166 (100-300mg/kg body) to SCID mice had no side effect. The concentration of 200mg/kg body MMI-166 inhibited the tumor growth in subcutaneous model, and slightly inhibited lymphogenous metastasis to the mediastinum in lymphogenous metastatic model. These results indicate that selective MMP inhibitors inhibit not only angiogenesis but also tumor invasion.