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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: Chemical synthesis, mechanistic studies, and effectiveness in vivo
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Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: Chemical synthesis, mechanistic studies, and effectiveness in vivo

机译：新型金（I）-磷抑制剂GoPI糖的抗神经胶质瘤活性：化学合成，机理研究和体内有效性

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摘要

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2- pyridyl)phosphole gold chloride thio-β-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430 μM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3 nM) and human glutathione reductase (IC 50 88.5 nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
机译：胶质母细胞瘤是一种侵袭性脑肿瘤，预后差，复发风险高。需要改进的化学治疗方法来补充放射治疗。带有磷脂配体的Gold（I）配合物是治疗癌症的有前途的药物，并通过抑制二硫键还原酶干扰癌细胞的氧化还原平衡和增殖。在这里，我们报告金（I）配合物1-苯基-双（2-吡啶基）磷酰氯硫代-β-d-葡萄糖四乙酸盐（GoPI-糖）的抗肿瘤特性，它对人（NCH82）具有抗增殖作用（NCH89）和大鼠（C6）胶质瘤细胞系。与卡莫斯汀（BCNU）（一种已建立的用于治疗胶质母细胞瘤的亚硝基脲化合物）相比，其抑制这些胶质瘤细胞系增殖的IC50为430μM，GoPI糖的疗效提高了两个数量级。此外，GoPI糖在C6胶质瘤大鼠模型中抑制体内恶性胶质瘤的生长，并显着减少肿瘤体积，同时具有良好的耐受性。金（I）氯和硫糖取代的磷脂均与DNA相互作用，尽管后者的DNA相互作用较弱。此外，GoPI糖不可逆地有效抑制硫氧还蛋白还原酶（IC50 4.3 nM）和人谷胱甘肽还原酶（IC 50 88.5 nM）。但是，用GoPI糖进行的治疗不会明显改变治疗动物脑组织中的氧化还原参数。这可能是由于氧化还原相关酶的代偿性上调，但也可能表明GoPI糖在体内的抗增殖作用是基于DNA相互作用和拓扑异构酶I的抑制，而不是基于氧化还原平衡的干扰。由于GoPI糖对胶质母细胞瘤非常有效且耐受性很强，因此它代表了药物开发的最有希望的领先者。本文是一个名为“基于硫醇的氧化还原过程”的特刊的一部分。

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