Selective Inhibition of Deamidated Triosephosphate Isomerase by Disulfiram, Curcumin, and Sodium Dichloroacetate: Synergistic Therapeutic Strategies for T-Cell Acute Lymphoblastic Leukemia in Jurkat Cells
Luis A. Flores-López,
Ignacio De la Mora-De la Mora,
Claudia M. Malagón-Reyes,
Itzhel García-Torres,
Yoalli Martínez-Pérez,
Gabriela López-Herrera,
Gloria Hernández-Alcántara,
Gloria León-Avila,
Gabriel López-Velázquez,
Alberto Olaya-Vargas,
Saúl Gómez-Manzo,
Sergio Enríquez-Flores
Affiliations
Luis A. Flores-López
Laboratorio de Biomoléculas y Salud Infantil, CONAHCYT-Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Ignacio De la Mora-De la Mora
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Claudia M. Malagón-Reyes
Posgrado en Ciencias Biológicas, (Maestría), Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
Itzhel García-Torres
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Yoalli Martínez-Pérez
Instituto Tecnológico y de Estudios Superiores de Monterrey, Campus Ciudad de México, Mexico City 14380, Mexico
Gabriela López-Herrera
Laboratorio de Inmunodeficiencias, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Gloria Hernández-Alcántara
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Apartado Postal 70-159, Mexico City 04510, Mexico
Gloria León-Avila
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
Gabriel López-Velázquez
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Alberto Olaya-Vargas
Trasplante de Células Madre y Terapia Celular, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Saúl Gómez-Manzo
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
Sergio Enríquez-Flores
Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
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.