Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors

Autor(es)

Carlos, Jorge Antonio Elias Godoy ; Tavares, Mauricio Temotheo ; Lima, Keli ; de Almeida, Larissa Costa ; Waitman, Karoline de Barros ; Costa-Lotufo, Leticia Veras ; Parise-Filho, Roberto ; Machado-Neto, Joao Agostinho

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH DISCOVERY; v. 11, n. 1, p. 11-pg., 2025-04-06.

Resumo

Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies. (AU)

• Processo FAPESP: 21/06138-0 - Caracterização da atividade de potenciais inibidores de histona desacetilase (HDAC) em modelos pré-clínicos de neoplasias hematólogicas
• Beneficiário: Jorge Antonio Elias Godoy Carlos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/08260-8 - Planejamento, síntese e avaliação biológica de inibidores híbridos de fosfoinositídeo 3-quinases e histona desacetilase 6 com vistas ao tratamento de neoplasias hematológicas
• Beneficiário: Roberto Parise Filho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 24/07723-2 - Otimização de inibidores híbridos de JAK3/HDAC6: planejamento, síntese e avaliação biológica
• Beneficiário: Roberto Parise Filho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/11606-3 - Investigação dos efeitos antineoplásicos de novos inibidores de PIP4K2 e HDAC em neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 23/12246-6 - Avaliação dos efeitos antineoplásicos do inibidor multiquinase AD80 em neoplasias hematológicas com ativação constitutiva de vias tirosina-quinase
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular