Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
Int Immunopharmacol. 2013 Sep;17(1):148-53. doi: 10.1016/j.intimp.2013.06.001. Epub 2013 Jun 14.
Many previous studies in animal models and clinical investigations have suggested that statins are useful chemotherapeutics against rheumatoid arthritis, whereas in vitro experiments using synovial cell lines showed no significant effect of statins on cell proliferation until now. Since synovial fluid in rheumatoid joint knee was found to be acidic, we examined the effect of statins on human synovial sarcoma cell line SW982 cells in acidic medium. Statins suppressed the proliferation of SW982 cells at pH6.7, while the suppression was very weak in pH7.5 medium. It was shown that the suppression was caused by the decrease in geranylgeranyl diphosphate, suggesting that a geranylgeranylated protein(s) has an essential role in cell proliferation of SW982 cells under acidic conditions. Our present data clearly implied that statins had high efficacy against SW982 cells in acidic medium whose pH is close to that of rheumatoid arthritis loci in patients. These results lead us to anticipate that screening of chemicals having high therapeutic efficacy in acidic medium promotes the development of new microenvironment-dependent medicines for chemotherapies against rheumatoid arthritis.
许多先前在动物模型和临床研究中的研究表明，他汀类药物是治疗类风湿关节炎的有用化疗药物，而到目前为止，使用滑膜细胞系的体外实验表明他汀类药物对细胞增殖没有显著影响。由于在类风湿性关节炎膝关节的滑液中发现是酸性的，因此我们在酸性介质中检查了他汀类药物对人滑膜肉瘤细胞系 SW982 细胞的影响。他汀类药物在 pH6.7 时抑制 SW982 细胞的增殖，而在 pH7.5 培养基中抑制作用非常弱。结果表明，这种抑制是由于香叶基香叶基二磷酸的减少引起的，这表明香叶酰香叶酰基化蛋白（s）在酸性条件下对 SW982 细胞的增殖起着至关重要的作用。我们目前的数据清楚地表明，在接近患者类风湿关节炎病灶 pH 值的酸性介质中，他汀类药物对 SW982 细胞具有很高的疗效。这些结果使我们预计，筛选在酸性介质中具有高治疗效果的化学物质将促进开发针对类风湿关节炎的新的依赖于微环境的化疗药物。
