Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival
Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to ven...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/3/461 |
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| author | Hind A. Alkhatabi Samir F. Zohny Mohammed Razeeth Shait Mohammed Hani Choudhry Mohd Rehan Aamir Ahmad Farid Ahmed Mohammad Imran Khan |
| author_facet | Hind A. Alkhatabi Samir F. Zohny Mohammed Razeeth Shait Mohammed Hani Choudhry Mohd Rehan Aamir Ahmad Farid Ahmed Mohammad Imran Khan |
| author_sort | Hind A. Alkhatabi |
| collection | DOAJ |
| description | Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML. |
| first_indexed | 2024-03-09T13:53:03Z |
| format | Article |
| id | doaj.art-69e02b1fb97a4ee0b38ea800bb0836f9 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T13:53:03Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-69e02b1fb97a4ee0b38ea800bb0836f92023-11-30T20:47:35ZengMDPI AGAntioxidants2076-39212022-02-0111346110.3390/antiox11030461Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for SurvivalHind A. Alkhatabi0Samir F. Zohny1Mohammed Razeeth Shait Mohammed2Hani Choudhry3Mohd Rehan4Aamir Ahmad5Farid Ahmed6Mohammad Imran Khan7Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaKing Fahd Medical Research Centre, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi ArabiaTranslational Research Institute, Hamad Medical Corporation, Doha 3050, QatarCenter of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaVenetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML.https://www.mdpi.com/2076-3921/11/3/461venetoclaxacute myeloid leukemiaMV4-11venetoclax resistance modelmetabolomicsPI3K/AKT pathway |
| spellingShingle | Hind A. Alkhatabi Samir F. Zohny Mohammed Razeeth Shait Mohammed Hani Choudhry Mohd Rehan Aamir Ahmad Farid Ahmed Mohammad Imran Khan Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival Antioxidants venetoclax acute myeloid leukemia MV4-11 venetoclax resistance model metabolomics PI3K/AKT pathway |
| title | Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival |
| title_full | Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival |
| title_fullStr | Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival |
| title_full_unstemmed | Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival |
| title_short | Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival |
| title_sort | venetoclax resistant mv4 11 leukemic cells activate pi3k akt pathway for metabolic reprogramming and redox adaptation for survival |
| topic | venetoclax acute myeloid leukemia MV4-11 venetoclax resistance model metabolomics PI3K/AKT pathway |
| url | https://www.mdpi.com/2076-3921/11/3/461 |
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