Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors

Author(s)

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

• Document type: Journal article
• Source: CELL DEATH DISCOVERY; v. 11, n. 1, p. 11-pg., 2025-04-06.

Abstract

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)

• FAPESP's process: 21/06138-0 - Characterization of the activity of potential histone deacetylase (HDAC) inhibitors in preclinical models of hematologic malignancies
• Grantee: Jorge Antonio Elias Godoy Carlos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/08260-8 - Design, synthesis and biological evaluation of hybrid inhibitors of phosphoinositide 3-kinases and histone deacetylase 6 for the treatment of hematologic malignancies
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 24/07723-2 - Optimization of hybrid inhibitors for JAK3/HDAC6: design, synthesis, and biological evaluation
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 23/12246-6 - Evaluation of the antineoplastic effects of the multikinase inhibitor AD80 in hematologic malignancies with constitutive activation of tyrosine-kinase pathways
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants