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

一种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羟肟酸（BPHA）（Shionogi Co.）有效抑制MMP-2、-9和-14，但不抑制MMP-1、-3或-7和MMI-166（Shionogi Co.）其选择性地抑制MMP-2和MMP-9。采用体外侵袭实验检测了BPHA和MMI-166对肺癌细胞株Ma 10和纤维肉瘤细胞株HT-1080体外侵袭能力的抑制作用。明胶酶谱分析显示HT-1080细胞具有MMP-9和MMP-2的明胶酶活性。BPHA对HT-1080和Ma 10的迁移能力无抑制作用，但对HT-1080和Ma 10的体外侵袭能力有抑制作用，抑制率分别为63%和41%。MMI-166（16 μ M）抑制HT-1080（83.4%）和Ma 10（52.7%）的体外侵袭潜力。此外，我们还采用皮下种植模型和淋巴结转移模型研究了MMI-166对Ma 10细胞株肿瘤生长和淋巴结转移的抑制作用。MMI-166（100- 300 mg/kg体重）经口给药对SCID小鼠无不良反应。200 mg/kg体重的MMI-166对皮下移植瘤的生长有抑制作用，对淋巴转移瘤的纵隔淋巴转移有轻微抑制作用。这些结果表明，选择性MMP抑制剂不仅抑制血管生成，而且抑制肿瘤侵袭。

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.