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Glutamic Acid Increased Methotrexate Polyglutamation and Cytotoxicity in a CCRF-SB Acute Lymphoblastic Leukemia Cell Line

1
Unidad de Investigación Genética, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, 76010 Querétaro, Mexico
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Laboratorio de Investigación en Productos Naturales, Facultad de Química, Universidad Autónoma de Querétaro, 76010 Querétaro, Mexico
3
Instituto de Neurobiología, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
*
Author to whom correspondence should be addressed.
Medicina 2019, 55(12), 758; https://doi.org/10.3390/medicina55120758
Received: 1 October 2019 / Revised: 4 November 2019 / Accepted: 20 November 2019 / Published: 26 November 2019
Background and Objectives: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. The majority of patients respond to treatment, but those with resistant phenotypes suffer relapse or death. The antifolate methotrexate (MTX) is the most commonly used drug against ALL due to its efficacy. Once inside leukemic cells, MTX is metabolized into methotrexate polyglutamates (MTX-PG) by action of the enzyme folylpolyglutamate synthetase (FPGS), leading to a longer action compared to that of MTX alone. Materials and Methods: In this work, we demonstrated that the combination treatment of methotrexate and 5 and 10 mM glutamic acid could enhance methotrexate cytotoxicity in CCRF-SB (B-ALL) cells. In addition, MTX plus 20 mM glutamic acid was able to improve the synthesis of MTX-PG5. Results: All treatments induced an increase in FPGS expression compared to that of the control group. Furthermore, we detected different cellular expression patterns of FPGS in the different treatments. Conclusion: Based on these findings, we demonstrated that levels of methotrexate polyglutamates (MTX-PGs) could be a key determinant of methotrexate-induced cytotoxicity in CCRF-SB acute lymphoblastic leukemia cells. View Full-Text
Keywords: polyglutamates; cytotoxicity; polyglutamation; methotrexate polyglutamates; cytotoxicity; polyglutamation; methotrexate
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Mendoza-Santiago, A.; Becerra, E.; Garay, E.; Bah, M.; Berumen-Segura, L.; Escobar-Cabrera, J.; Hernández-Pérez, A.; García-Alcocer, G. Glutamic Acid Increased Methotrexate Polyglutamation and Cytotoxicity in a CCRF-SB Acute Lymphoblastic Leukemia Cell Line. Medicina 2019, 55, 758.

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