Rangel-López Edgar, Robles-Bañuelos Benjamín, Guadiana-Ramírez Natalia, Alvarez-Garduño Valeria, Galván-Arzate Sonia, Zazueta Cecilia, Karasu Cimen, Túnez Isaac, Tinkov Alexey, Aschner Michael, Santamaría Abel
Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico.
Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico.
Neurotox Res. 2022 Jun;40(3):814-824. doi: 10.1007/s12640-022-00514-6. Epub 2022 Apr 27.
Thallium (Tl) is a heavy metal that causes toxicity in several organs, including the brain. Its cytotoxic profile, combined with its affinity for tumor cells when used as a radioligand for labeling these cells, suggests its potential use as antitumor therapy. In this study, glioblastoma cell lines C6 (from rat) and U373 (from human) were exposed to increased concentrations of thallium(I) acetate (5, 10, 50, 100, or 200 µM) and several toxic endpoints were evaluated, including loss of confluence and morphological changes, loss of cell viability, changes in cell cycle, and apoptosis. Tl was detected in cells exposed to thallium(I) acetate, demonstrating efficient uptake mechanism. Confluence in both cell lines decreased in a concentration-dependent manner (50-200 µM), while morphological changes (cell shrinkage and decreased cell volume) were more evident at exposures to higher Tl concentrations. For both parameters, the effects of Tl were more prominent in C6 cells compared to U373 cells. The same trend was observed for cell viability, with Tl affecting this parameter in C6 cells at low concentrations, whereas U373 cells showed greater resistance, with significant changes observed only at the higher concentrations. C6 and U373 cells treated with Tl also showed morphological characteristics corresponding to apoptosis. The cytotoxic effects of Tl were also assessed in neural and astrocytic primary cultures from the whole rat brain. Primary neural and astrocytic cultures were less sensitive than C6 and U373 cells, showing changes in cell viability at 50 and 100 µM concentrations, respectively. Cell cycle in both brain tumor cell lines was altered by Tl in G1/G2 and S phases. In addition, when combined with temozolamide (500 µM), Tl elicited cell cycle alterations, increasing SubG1 population. Combined, our novel results characterize and validate the cytotoxic and antiproliferative effects of Tl in glioblastoma cells.
铊（Tl）是一种重金属，可对包括大脑在内的多个器官产生毒性。其细胞毒性特征，以及在用作标记肿瘤细胞的放射性配体时对肿瘤细胞的亲和力，表明其具有作为抗肿瘤疗法的潜在用途。在本研究中，将胶质母细胞瘤细胞系C6（来自大鼠）和U373（来自人类）暴露于浓度递增的醋酸铊（I）（5、10、50、100或200μM）中，并评估了几个毒性终点，包括汇合度丧失和形态变化、细胞活力丧失、细胞周期变化和细胞凋亡。在暴露于醋酸铊（I）的细胞中检测到了铊，证明存在有效的摄取机制。两种细胞系的汇合度均呈浓度依赖性降低（50 - 200μM），而形态变化（细胞收缩和细胞体积减小）在暴露于较高铊浓度时更为明显。对于这两个参数，与U373细胞相比，铊对C6细胞的影响更为显著。细胞活力也观察到相同趋势，低浓度时铊影响C6细胞的这一参数，而U373细胞表现出更大的抗性，仅在较高浓度时才观察到显著变化。用铊处理的C6和U373细胞也表现出与细胞凋亡相对应的形态特征。还在来自整个大鼠脑的神经和星形胶质细胞原代培养物中评估了铊的细胞毒性作用。原代神经和星形胶质细胞培养物比C6和U373细胞更不敏感，分别在50和100μM浓度时显示出细胞活力变化。铊改变了两种脑肿瘤细胞系在G1/G2和S期的细胞周期。此外，当与替莫唑胺（500μM）联合使用时，铊引发细胞周期改变，增加了亚G1期细胞群体。综合来看，我们的新结果表征并验证了铊在胶质母细胞瘤细胞中的细胞毒性和抗增殖作用。
