Weisz B, Giehl K, Gana-Weisz M, Egozi Y, Ben-Baruch G, Marciano D, Gierschik P, Kloog Y
Department of Neurobiochemistry, The George S Wise Faculty of Life Sciences, Tel-Aviv University, Israel.
Oncogene. 1999 Apr 22;18(16):2579-88. doi: 10.1038/sj.onc.1202602.
Constitutively active Ras proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Ras, are frequently associated with cell transformation in human tumors. This suggests that functional Ras antagonists may have anti-tumor activity. Studies in rodent fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Ras antagonist, dislodging Ras from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase inhibitor, and does not affect Ras maturation. Here we demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells, FTS at a concentration of 25-100 microM reduced the amount of Ras in a dose-dependent manner and interfered with serum-dependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm3) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23+/-30-fold in the FTS-treated group and by 127+/-66-fold in controls). These findings suggest that FTS represents a new class of functional Ras antagonists with potential therapeutic value.
组成型激活的Ras蛋白、其调节成分以及激活Ras的过表达酪氨酸激酶受体，在人类肿瘤中常与细胞转化相关。这表明功能性Ras拮抗剂可能具有抗肿瘤活性。对啮齿动物成纤维细胞的研究表明，S-反式、反式法尼基硫代水杨酸（FTS）作为一种相当特异的无毒Ras拮抗剂，可将Ras从其膜锚定结构域中解离出来并加速其降解。FTS不是法尼基转移酶抑制剂，不影响Ras的成熟。在此我们证明，FTS在表达激活型K-Ras的人胰腺细胞系（Panc-1和MiaPaCa-2）中也作为一种功能性Ras拮抗剂发挥作用。在Panc-1细胞中，浓度为25 - 100 microM的FTS以剂量依赖方式减少Ras的量，并干扰血清依赖性和表皮生长因子刺激的ERK激活，从而在体外抑制Panc-1细胞的贴壁依赖性和非贴壁依赖性生长。FTS还抑制Panc-1异种移植裸鼠中的肿瘤生长，显然无全身毒性。对患有肿瘤（平均体积0.07 cm3）的小鼠每日进行FTS处理（腹腔注射5 mg/kg）可显著降低肿瘤生长（处理18天后，FTS处理组肿瘤体积仅增加23±30倍，而对照组增加127±66倍）。这些发现表明，FTS代表了一类具有潜在治疗价值的新型功能性Ras拮抗剂。
