Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy.
PhD Program in Neuroscience, University of Milano-Bicocca, Monza, Italy.
Neurotox Res. 2018 Jul;34(1):93-108. doi: 10.1007/s12640-018-9864-8. Epub 2018 Jan 17.
[Cu(thp)]PF, [Cu(PTA)]PF, [Au(thp)]PF and [Au(PTA)]PF are phosphane (thp = tris(hydroxymethyl)phosphane; PTA = 1,3,5-triaza-7-phosphaadamantane) copper(I) and gold(I) water-soluble complexes characterized by high anticancer activity in a wide range of solid tumors, often able to overcome drug resistance of platinum-based compounds. For these reasons, they have been proposed as a valid alternative to platinum-based chemotherapeutic drugs (e.g., cisplatin and oxaliplatin). In vitro experiments performed on organotypic cultures of dorsal root ganglia (DRG) from 15-day-old rat embryos revealed that copper-based compounds were not neurotoxic even at concentrations higher than the IC obtained in human cancer cells while [Au(PTA)]PF was neurotoxic at lower concentration than IC in cancer cell lines. The ability of these compounds to hinder the proteasome machinery in DRG neurons was tested by fluorimetric assay showing that the non-neurotoxic copper-based complexes do not inhibit proteasome activity in DRG primary neuron cultures. On the contrary, the neurotoxic complex [Au(PTA)]PF, induced a significant inhibition of proteasome activity even at concentrations lower than the IC in cancer cells. The proteasome inhibition induced by [Au(PTA)]PF was associated with a significant increase in α-tubulin polymerization that was not observed following the treatment with copper-based compounds. Uptake experiments performed by atomic absorption spectrometry showed that both copper-based complexes and [Au(PTA)]PF are internalized in neuron cultures. In vitro and in vivo preliminary data confirmed copper-based complexes as the most promising compounds, not only for their anticancer activity but also concerning the peripheral neurotoxicity profile.
[Cu(thp)]PF、[Cu(PTA)]PF、[Au(thp)]PF 和 [Au(PTA)]PF 是膦（thp = 三羟甲基膦；PTA = 1,3,5-三氮杂-7-磷金刚烷）铜（I）和金（I）水溶性配合物，具有广泛的固体肿瘤高抗癌活性，通常能够克服铂类化合物的耐药性。由于这些原因，它们已被提议作为铂类化疗药物（例如顺铂和奥沙利铂）的有效替代品。在 15 天大的大鼠胚胎背根神经节（DRG）器官型培养物上进行的体外实验表明，即使在高于人癌细胞中获得的 IC 的浓度下，铜基化合物也没有神经毒性，而 [Au(PTA)]PF 在低于癌细胞系中 IC 的浓度下具有神经毒性。通过荧光测定法测试这些化合物在 DRG 神经元中抑制蛋白酶体机制的能力，结果表明非神经毒性铜基配合物不会抑制 DRG 原代神经元培养物中的蛋白酶体活性。相反，神经毒性复合物 [Au(PTA)]PF 即使在低于癌细胞中 IC 的浓度下，也会诱导蛋白酶体活性的显著抑制。[Au(PTA)]PF 诱导的蛋白酶体抑制与α-微管蛋白聚合的显著增加相关，在用铜基化合物处理后未观察到这种情况。原子吸收光谱法进行的摄取实验表明，铜基配合物和 [Au(PTA)]PF 都被内化到神经元培养物中。体外和体内初步数据证实铜基配合物是最有前途的化合物，不仅因为它们的抗癌活性，还因为它们的周围神经毒性特征。
