Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Cancer Lett. 2010 Nov 28;297(2):182-9. doi: 10.1016/j.canlet.2010.05.010. Epub 2010 Jun 17.
In tumor cell masses, the extracellular pH decreases below 6.5. The effect of external acidic pH on the efficacy of 24 chemical compounds including molecular-targeted inhibitors and anti-tumor reagents was investigated in human cancer cells. Lovastatin showed no cytotoxicity in mesothelioma or pancreatic carcinoma cells at concentrations up to 10 μM and pH around 7.4, but 10 μM lovastatin decreased the survival of these cells below 40% at acidic pH. Lovastatin inhibits HMG-CoA reductase, resulting in a decrease in the levels of cholesterol and prenylated proteins. An inhibitor of the former pathway showed pH-independent cytotoxic activity, whereas an inhibitor of the latter pathway had stronger activity at acidic pH. The inhibitory efficacy of cantharidin also increased at acidic pH. On the other hands, no pH dependency or slightly impaired efficacy at low pH conditions was observed in other 20 reagents, and especially, the activity of aphidicolin was suppressed under acidic conditions. These results suggested that screening under acidic conditions would be useful for developing new chemotherapeutic reagents.
在肿瘤细胞群中，细胞外 pH 值会下降到 6.5 以下。研究人员在人类癌细胞中研究了外部酸性 pH 值对包括分子靶向抑制剂和抗肿瘤试剂在内的 24 种化学化合物的功效的影响。洛伐他汀在浓度高达 10 μM 且 pH 值接近 7.4 的情况下，对间皮瘤或胰腺癌细胞没有细胞毒性，但在酸性 pH 值下，10 μM 的洛伐他汀将这些细胞的存活率降低到 40%以下。洛伐他汀抑制 HMG-CoA 还原酶，导致胆固醇和异戊烯基蛋白水平降低。前者途径的抑制剂表现出与 pH 值无关的细胞毒性活性，而后者途径的抑制剂在酸性 pH 值下具有更强的活性。斑蝥素的抑制效果也在酸性 pH 值下增加。另一方面，其他 20 种试剂在酸性条件下没有表现出 pH 依赖性或活性略有降低，尤其是阿非迪可林在酸性条件下的活性受到抑制。这些结果表明，在酸性条件下进行筛选可能有助于开发新的化疗试剂。
