Targeting G6PD with Benzimidazole and Thiazole Derivatives Suppresses SIRT 2 and VEGF Expression and Induces Cytotoxicity in Glioma Cells
Por:
Vázquez-Bautista, M, Morales-Luna, L, de la Cruz, VP, Castillo-Rodriguez, RA, Velázquez-Aragón, JA, Enriquez-Flores, S, Flores-López, LA, Hernández-Urzúa, E, Martinez-Rosas, V, Wong-Baeza, C, Baeza-Ramirez, I, Navarrete-Vázquez, G, Pineda, B, Hernández-Ochoa, B, Gómez-Manzo, S
Publicada:
18 sep 2025
Resumen:
Hypoxia and activation of the pentose phosphate pathway (PPP), as well as overexpression of glucose-6-phosphate dehydrogenase (G6PD), are hallmark features of glioblastomas (GBM), contributing significantly to tumor progression metabolic adaptation and drug resistance. This study aimed to evaluate the cytotoxic effects of nine synthetic compounds incorporating annulated benzimidazole and nitrothiazole scaffolds in two glioblastoma cell lines (A172 and U87-MG) under both normoxic and hypoxic conditions. Three compounds (BZM-7, BZM-9, and CNZ-3) demonstrated potent anticancer activity, with CNZ-3 exhibiting the highest efficacy, particularly in hypoxia. The study further investigated the effects of these compounds on the expression of the G6PD gene, as well as post-translational regulatory genes SIRT2 and KAT9, and the angiogenesis-related VEGF gene. Transcriptional analyses showed that the nitrothiazole-derived compound CNZ-3 significantly downregulated G6PD, SIRT2, KAT9 and VEGF expression under hypoxic conditions, suggesting selective interference with hypoxia-adaptative pathways. In contrast, BZM-7 and BZM-9 showed distinct expression patterns, indicating diverse mechanisms of action despite structural similarity. In addition, BZM-7, BZM-9, and CNZ-3 were identified as potent inhibitors of recombinant G6PD, demonstrating both enzymatic inhibition and structural alterations, suggesting that G6PD could be a relevant therapeutic target for these compounds. Furthermore, molecular docking analysis revealed favorable binding interactions between the compounds and key amino acids of the G6PD, reinforcing their potential as a direct enzyme inhibitors. These findings highlight the pivotal role of G6PD in gliomas under hypoxic conditions and support its inhibition as a promising therapeutic strategy.
Filiaciones:
Vázquez-Bautista, M:
Inst Nacl Pediat, Lab Bioquim Genet, Secretaria Salud, Mexico City 04530, Mexico
Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Programa Posgrad Biomed & Biotecnol Mol, Mexico City 11340, Mexico
Morales-Luna, L:
Inst Nacl Pediat, Lab Bioquim Genet, Secretaria Salud, Mexico City 04530, Mexico
Univ Nacl Autonoma Mexico, Posgrad Ciencias Biol, Mexico City 04510, Mexico
de la Cruz, VP:
Natl Inst Neurol & Neurosurg Manuel Velasco Suarez, Neurobiochem & Behav Lab, Mexico City 14269, Mexico
Castillo-Rodriguez, RA:
Inst Politecn Nacl, Ctr Invest Ciencia Aplicada & Tecnol Avanzada CICA, Unidad Morelos, Blvd Tecnol 1036 Z-1,P 2-2, Atlacholoaya 62790, Mexico
Velázquez-Aragón, JA:
Inst Nacl Pediat, Lab Oncol Expt, Ciudad de Mexico 04530, Mexico
Enriquez-Flores, S:
Inst Nacl Pediat, Lab Biomol & Salud Infantil, Secretaria Salud, Mexico City 04530, Mexico
Flores-López, LA:
Inst Nacl Pediat, Secretaria Salud, Secretaria Ciencia Humanidades Tecnol & Innovac SE, Mexico City 04530, Mexico
Hernández-Urzúa, E:
Inst Nacl Pediat, Lab Toxicol Genet, Secretaria Salud, Mexico City 04530, Mexico
Martinez-Rosas, V:
Tecnol Nacl Mexico, Inst Tecnol Milpa Alta, Dept Ingn Quim & Bioquim, Mexico City 12300, Mexico
Wong-Baeza, C:
Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Dept Bioquim, Lab Biomembranas, Mexico City 11350, Mexico
Baeza-Ramirez, I:
Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Dept Bioquim, Lab Biomembranas, Mexico City 11350, Mexico
Navarrete-Vázquez, G:
Univ Autonoma Estado Morelos, Fac Farm, Cuernavaca 62209, Mexico
Pineda, B:
Natl Inst Neurol & Neurosurg Manuel Velasco Suarez, Neuroimmunol Lab, Mexico City 14269, Mexico
Hernández-Ochoa, B:
Hosp Infantil Mexico Dr Federico Gomez, Lab Inmunoquim, Secretaria Salud, Mexico City 06720, Mexico
Gómez-Manzo, S:
Inst Nacl Pediat, Lab Bioquim Genet, Secretaria Salud, Mexico City 04530, Mexico
Green Submitted, gold, All Open Access; Gold Open Access; Green Accepted Open Access; Green Open Access
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