Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors
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) i...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02446-4 |
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| _version_ | 1850268630263005184 |
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| author | Jorge Antonio Elias Godoy Carlos Mauricio Temotheo Tavares Keli Lima Larissa Costa de Almeida Karoline de Barros Waitman Leticia Veras Costa-Lotufo Roberto Parise-Filho João Agostinho Machado-Neto |
| author_facet | Jorge Antonio Elias Godoy Carlos Mauricio Temotheo Tavares Keli Lima Larissa Costa de Almeida Karoline de Barros Waitman Leticia Veras Costa-Lotufo Roberto Parise-Filho João Agostinho Machado-Neto |
| author_sort | Jorge Antonio Elias Godoy Carlos |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8fa84e2d6a904490aab84c1e4c820cb2 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-8fa84e2d6a904490aab84c1e4c820cb22025-08-20T01:53:23ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111110.1038/s41420-025-02446-4Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitorsJorge Antonio Elias Godoy Carlos0Mauricio Temotheo Tavares1Keli Lima2Larissa Costa de Almeida3Karoline de Barros Waitman4Leticia Veras Costa-Lotufo5Roberto Parise-Filho6João Agostinho Machado-Neto7Department of Pharmacology, Institute of Biomedical Sciences, University of São PauloDepartment of Pharmacy, Faculty of Pharmaceutical Science, University of São PauloDepartment of Pharmacology, Institute of Biomedical Sciences, University of São PauloDepartment of Pharmacology, Institute of Biomedical Sciences, University of São PauloDepartment of Pharmacy, Faculty of Pharmaceutical Science, University of São PauloDepartment of Pharmacology, Institute of Biomedical Sciences, University of São PauloDepartment of Pharmacy, Faculty of Pharmaceutical Science, University of São PauloDepartment of Pharmacology, Institute of Biomedical Sciences, University of São PauloAbstract 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.https://doi.org/10.1038/s41420-025-02446-4 |
| spellingShingle | Jorge Antonio Elias Godoy Carlos Mauricio Temotheo Tavares Keli Lima Larissa Costa de Almeida Karoline de Barros Waitman Leticia Veras Costa-Lotufo Roberto Parise-Filho João Agostinho Machado-Neto Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors Cell Death Discovery |
| title | Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors |
| title_full | Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors |
| title_fullStr | Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors |
| title_full_unstemmed | Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors |
| title_short | Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors |
| title_sort | enhancing venetoclax efficacy in leukemia through association with hdac inhibitors |
| url | https://doi.org/10.1038/s41420-025-02446-4 |
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