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

MMP抑制剂BPHA抑制人肺癌细胞肿瘤生长和转移的潜力

基本信息

批准号：
11671328
负责人：
KONDO Kazuya
金额：
$ 2.24万
依托单位：
The university of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671328/
关键词：
MMP inhibitor lung cancer tumor invasion BPHA MM1-166 Haptoinvasion assay MMI-166 MMP-2 浸潤阻害 in vitro invasion assay

项目摘要

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.

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.）对MMP-2、-9和-14有抑制作用，但对MMP-1、-3或-7无抑制作用，对MMP-2、-9有选择性抑制作用。采用体外接触侵袭法研究BPHA和MMI-166对肺癌细胞系Ma10和纤维肉瘤细胞系HT-1080体外侵袭潜能的抑制作用。经明胶酶谱分析，HT-1080细胞株具有MMP-9和MMP-2的溶胶活性。另一方面，Ma10细胞系具有MMP-2的溶胶活性，而不具有MMP-9的溶胶活性。虽然BPHA没有抑制HT-1080和Ma10的迁移潜力，但它抑制了HT-1080（63%）和Ma10（41%）的体外侵袭潜力。MMI-166 （16 μ m）抑制HT-1080（83.4%）和Ma10（52.7%）的体外侵袭潜力。此外，我们还通过皮下植入模型和淋巴转移模型研究了MMI-166对Ma10细胞株肿瘤生长和淋巴结转移的抑制作用。对SCID小鼠口服MMI-166 （100-300mg/kg体）无不良反应。在皮下模型中，浓度为200mg/kg的MMI-166对肿瘤生长有抑制作用；在淋巴转移模型中，浓度为200mg/kg的MMI-166对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。