Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival
| Autor: | Hind A. Alkhatabi, Samir F. Zohny, Mohammed Razeeth Shait Mohammed, Hani Choudhry, Mohd Rehan, Aamir Ahmad, Farid Ahmed, Mohammad Imran Khan |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Antioxidants, Vol 11, Iss 3, p 461 (2022) |
| Druh dokumentu: | article |
| ISSN: | 11030461 2076-3921 |
| DOI: | 10.3390/antiox11030461 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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