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Thallium Induces Antiproliferative and Cytotoxic Activity in Glioblastoma C6 and U373 Cell Cultures via Apoptosis and Changes in Cell Cycle

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Abstract

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. 

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Funding

MA was supported in part by grants from the National Institute of Environmental Health Sciences, R01ES03771 and R01ES10563. CK was supported by TUBITAK grant 315S088.

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Authors and Affiliations

  1. Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico

    Edgar Rangel-López, Benjamín Robles-Bañuelos, Natalia Guadiana-Ramírez, Valeria Alvarez-Garduño & Abel Santamaría

  2. Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico

    Sonia Galván-Arzate

  3. Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico

    Cecilia Zazueta

  4. Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler, 06500, Turkey

    Cimen Karasu

  5. Instituto de Investigaciones Biomédicas Maimonides de Córdoba (IMIBIC), Córdoba, Spain

    Isaac Túnez

  6. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Universidad de Córdoba, Córdoba, Spain

    Isaac Túnez

  7. Red Española de Excelencia en Estimulación Cerebral (REDESTIM), Córdoba, Spain

    Isaac Túnez

  8. IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

    Alexey Tinkov

  9. Yaroslavl State University, Yaroslavl, Russia

    Alexey Tinkov

  10. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Michael Aschner

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  1. Edgar Rangel-López
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Correspondence to Edgar Rangel-López or Abel Santamaría.

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Rangel-López, E., Robles-Bañuelos, B., Guadiana-Ramírez, N. et al. Thallium Induces Antiproliferative and Cytotoxic Activity in Glioblastoma C6 and U373 Cell Cultures via Apoptosis and Changes in Cell Cycle. Neurotox Res 40, 814–824 (2022). https://doi.org/10.1007/s12640-022-00514-6

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