Laboratory of Molecular Pathology of Cancer, University of Brasilia Brasilia, Brazil.
Laboratory of Clinical and Toxicological Analysis, São Rafael Hospital Salvador, Brazil.
Front Cell Neurosci. 2014 Sep 30;8:308. doi: 10.3389/fncel.2014.00308. eCollection 2014.
The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.
血脑屏障（BBB）被认为可以保护健康的脑细胞免受潜在的危险化学物质的侵害，但有许多证据支持这样一种观点，即这种保护作用延伸到肿瘤细胞。由于脑肿瘤中的血管生成过程导致 BBB 破裂，因此 BBB 的生化特征似乎比物理屏障更能保护肿瘤细胞免受化疗的影响。事实上，已经有许多与耐药性相关的因素被证明是 BBB 和肿瘤细胞的组成部分。谷胱甘肽 S-转移酶（GST）可以解毒亲电的外来化学物质和氧化应激过程中形成的内源性次级代谢物。GST 被认为在癌细胞对化疗药物的耐药性中起作用。本研究将 8-甲氧基补骨脂素（8-MOP）鉴定为人类 GST P1-1（hGST P1-1）抑制剂。为了确定和表征 8-MOP 的潜在抑制活性，我们研究了 hGST P1-1 催化 GSH 与 1-氯-2,4-二硝基苯（CDNB）结合的酶动力学。我们在这里报告 8-MOP 竞争性地抑制 hGST P1-1 相对于 CDNB，但相对于 GSH 存在非竞争性抑制。色谱分析表明 8-MOP 不是底物。分子对接模拟表明 8-MOP 结合到活性位点，但它的位置阻止了 GSH 的结合。因此，我们得出结论，8-MOP 是一种有前途的 GST 抑制剂原型，在治疗神经退行性疾病和癌症对化疗的耐药性方面具有潜在的药理学应用价值。
