Selective Inhibition of Deamidated Triosephosphate Isomerase by Disulfiram, Curcumin, and Sodium Dichloroacetate: Synergistic Therapeutic Strategies for T-Cell Acute Lymphoblastic Leukemia in Jurkat Cells
Por:
Flores-López L.A., De la Mora-De la Mora I., Malagón-Reyes C.M., García-Torres I., Martínez-Pérez Y., López-Herrera G., Hernández-Alcántara G., León-Avila G., López-Velázquez G., Olaya-Vargas A., Gómez-Manzo S., Enríquez-Flores S.
Publicada:
1 ene 2024
Resumen:
T-cell acute lymphoblastic leukemia (T-ALL) is a challenging childhood cancer to treat, with limited therapeutic options and high relapse rates. This study explores deamidated triosephosphate isomerase (dTPI) as a novel therapeutic target. We hypothesized that selectively inhibiting dTPI could reduce T-ALL cell viability without affecting normal T lymphocytes. Computational modeling and recombinant enzyme assays revealed that disulfiram (DS) and curcumin (CU) selectively bind and inhibit dTPI activity without affecting the non-deamidated enzyme. At the cellular level, treatment with DS and CU significantly reduced Jurkat T-ALL cell viability and endogenous TPI enzymatic activity, with no effect on normal T lymphocytes, whereas the combination of sodium dichloroacetate (DCA) with DS or CU showed synergistic effects. Furthermore, we demonstrated that dTPI was present and accumulated only in Jurkat cells, confirming our hypothesis. Finally, flow cytometry confirmed apoptosis in Jurkat cells after treatment with DS and CU or their combination with DCA. These findings strongly suggest that targeting dTPI represents a promising and selective target for T-ALL therapy. © 2024 by the authors.
Filiaciones:
Flores-López L.A.:
Laboratorio de Biomoléculas y Salud Infantil, CONAHCYT-Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
De la Mora-De la Mora I.:
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Malagón-Reyes C.M.:
Posgrado en Ciencias Biológicas, (Maestría), Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
García-Torres I.:
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Martínez-Pérez Y.:
Instituto Tecnológico y de Estudios Superiores de Monterrey, Campus Ciudad de México, Mexico City, 14380, Mexico
López-Herrera G.:
Laboratorio de Inmunodeficiencias, Instituto Nacional de Pediatría, México City, 04530, Mexico
Hernández-Alcántara G.:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Apartado Postal 70-159, Mexico City, 04510, Mexico
León-Avila G.:
Departamento de Zoología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Carpio y Plan de Ayala S/N, Casco de Santo Tomás, Ciudad de México, 11340, Mexico
López-Velázquez G.:
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Olaya-Vargas A.:
Trasplante de Células Madre y Terapia Celular, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Gómez-Manzo S.:
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
Enríquez-Flores S.:
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City, 04530, Mexico
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