Nakajima Masahide, Hayashi Kazutaka, Katayama Ken-ichi, Amano Yusaku, Egi Yasuhiro, Uehata Masayoshi, Goto Nobuharu, Kondo Takao
Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Kanagawa, 227-0033, Yokohama, Japan.
Eur J Pharmacol. 2003 Jan 17;459(2-3):113-20. doi: 10.1016/s0014-2999(02)02869-8.
The signaling pathway of Rho and Rho-associated coiled-coil forming protein kinase (ROCK) is involved in tumor metastasis. In the present study, we investigated the suppressive effect of a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-Aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride], on spontaneous tumor metastasis in vivo and analyzed its action on tumor cell motility and angiogenesis to clarify its action mechanism. Wf-536 (0.3-3 mg/kg/day) was found to inhibit Lewis lung carcinoma (LLC) metastasis and LLC-induced angiogenesis in orally treated mice; in vitro, it inhibited both invasion and migration by LLC cells and invasion, migration, and formation of capillary-like tubes on Matrigel by endothelial cells, without cytotoxicity or anti-proliferative action in either cell type. We conclude that Wf-536 has tumor anti-metastatic activity which may depend on inhibition of tumor motility and angiogenesis. The findings support its further clinical development as an anti-metastatic agent.
Rho及Rho相关卷曲螺旋形成蛋白激酶（ROCK）的信号通路参与肿瘤转移。在本研究中，我们研究了一种新型ROCK抑制剂Wf-536 [（+）-（R）-4-（1-氨基乙基）-N-（4-吡啶基）苯甲酰胺单盐酸盐]对体内自发性肿瘤转移的抑制作用，并分析了其对肿瘤细胞运动性和血管生成的作用，以阐明其作用机制。发现Wf-536（0.3 - 3mg/kg/天）可抑制经口服处理的小鼠体内Lewis肺癌（LLC）转移及LLC诱导的血管生成；在体外，它可抑制LLC细胞的侵袭和迁移以及内皮细胞在基质胶上的侵袭、迁移和类毛细血管样管的形成，且对两种细胞类型均无细胞毒性或抗增殖作用。我们得出结论，Wf-536具有肿瘤抗转移活性，这可能依赖于对肿瘤运动性和血管生成的抑制。这些发现支持其作为抗转移药物进一步开展临床研究。
