Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax
Copyright © 2024 Elsevier Inc. All rights reserved..
The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Biochemical pharmacology - (2024) vom: 17. Feb., Seite 116065 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhao, Jianlei [VerfasserIn] |
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| Links: |
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| Themen: |
Acute myeloid leukemia |
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| Anmerkungen: |
Date Revised 22.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.bcp.2024.116065 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368636542 |
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| 520 | |a The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute myeloid leukemia | |
| 650 | 4 | |a Azacitidine | |
| 650 | 4 | |a Panobinostat | |
| 650 | 4 | |a Venetoclax | |
| 700 | 1 | |a Wu, Shuangshuang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Deying |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Holly |e verfasserin |4 aut | |
| 700 | 1 | |a Thibodeau, Jenna |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Seongho |e verfasserin |4 aut | |
| 700 | 1 | |a Stemmer, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guan |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Jingji |e verfasserin |4 aut | |
| 700 | 1 | |a Savasan, Süreyya |e verfasserin |4 aut | |
| 700 | 1 | |a Taub, Jeffrey W |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Yubin |e verfasserin |4 aut | |
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