| Full text | |
| Author(s): Show less - |
de Queiroz, Gustavo Nery
;
Lima, Keli
;
Cipelli, Marcella
;
Tomaz, Victoria
;
Cortez, Luiz Gustavo Ferreira
;
Silvad, Marina de Franca Basto
;
Guedes, Rafael Lucas Muniz
;
Campregher, Paulo Vidal
;
Rego, Eduardo Magalhaes
;
Camara, Niels Olsen Saraiva
;
Costa-Lotufo, Leticia Veras
;
Machado-Neto, Joao Agostinho
Total Authors: 12
|
| Document type: | Journal article |
| Source: | BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE; v. 1872, n. 1, p. 12-pg., 2025-10-02. |
| Abstract | |
Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased oxidative phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/AKT/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML. (AU) | |
| FAPESP's process: | 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases |
| Grantee: | Niels Olsen Saraiva Câmara |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 23/01331-2 - Investigation of potential molecular targets in models of acute myeloid leukemias with acquired resistance to venetoclax. |
| Grantee: | Gustavo Nery de Queiroz |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 23/08735-1 - ProspecMar network: prospecting marine natural resources |
| Grantee: | Leticia Veras Costa Lotufo |
| Support Opportunities: | BIOTA-FAPESP Program - Thematic 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 |
| 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: | 24/02796-1 - Prospecting biomarkers of response to antineoplastic agents and molecular and clinical-laboratory correlation in acute lymphoblastic leukemia using an ex vivo platform |
| Grantee: | Keli Cristina de Lima |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |