Department of Chemistry, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung, Taiwan 40227, ROC.
Bioorg Med Chem. 2010 Mar 1;18(5):1980-7. doi: 10.1016/j.bmc.2010.01.031. Epub 2010 Jan 18.
Enediyne anticancer drugs belong to one of the most potent category in inducing DNA damage. We report 85+/-5% inhibition on activity of neocarzinostatin by salt. As high sodium ion concentration is a known tumor cell feature, we explored the dynamic mechanism of inhibition. Using various analytical tools, we examined parameters involved in the four consecutive steps of the drug action, namely, drug releasing from carrier protein, drug-DNA binding, drug activating, and DNA damaging. Neither protein stability, nor drug release rate, was altered by salt. The salt inhibition level was similar in between the protein-bound and unbound enediyne chromophore. Salt did not quench the thiol-induced drug activation. The inhibition was independent of DNA lesion types and irrelevant with thiol structures. Collectively, no salt interaction was found in the releasing, activating, and DNA damaging step of the drug action. However, binding with DNA decreased linearly with salt and corresponded well with the salt-induced inhibition on the drug activity. Salt interference on the affinity of DNA binding was the main and sole cause of the severe salt inhibition. The inhibition factor should be carefully considered for all agents with similar DNA binding mode.
烯二炔类抗癌药物属于诱导 DNA 损伤的最有效类别之一。我们报告盐对新制癌菌素活性的抑制率为 85+/-5%。由于高钠离子浓度是已知的肿瘤细胞特征，我们探索了抑制的动态机制。使用各种分析工具，我们检查了药物作用的四个连续步骤中涉及的参数，即载体蛋白释放药物、药物-DNA 结合、药物激活和 DNA 损伤。盐既没有改变蛋白质的稳定性，也没有改变药物的释放速率。盐对结合蛋白和未结合烯二炔生色团的抑制水平相似。盐没有猝灭巯基诱导的药物激活。抑制与 DNA 损伤类型无关，与巯基结构无关。总的来说，在药物作用的释放、激活和 DNA 损伤步骤中没有发现盐相互作用。然而，与 DNA 的结合随盐线性降低，与盐对药物活性的抑制作用非常吻合。盐对 DNA 结合亲和力的干扰是盐对药物活性产生严重抑制的主要和唯一原因。对于所有具有类似 DNA 结合模式的药物，都应仔细考虑抑制因子。
