Targeting NRF2 uncovered an intrinsic susceptibility of acute myeloid leukemia cells to ferroptosis

by Selleckchem | Jul 25 2023

Drug resistance and poor treatment response are major obstacles to the effective treatment of acute myeloid leukemia (AML). A deeper understanding of the mechanisms regulating drug resistance and response genes in AML is therefore urgently needed. Our previous research has highlighted the important role of nuclear factor E2-related factor 2 (NRF2) in AML, where it plays a critical role in detoxifying reactive oxygen species and influencing sensitivity to chemotherapy. In this study, we identify a core set of direct NRF2 targets that are involved in ferroptosis, a novel form of cell death. Of particular interest, we find that glutathione peroxidase 4 (GPX4) is a key ferroptosis gene that is consistently upregulated in AML, and high expression of GPX4 is associated with poor prognosis for AML patients. Importantly, simultaneous inhibition of NRF2 with ML385 and GPX4 with FIN56 or RSL3 synergistically targets AML cells, triggering ferroptosis. Treatment with ML385 + FIN56/RSL3 resulted in a marked reduction in NRF2 and GPX4 expression. Furthermore, NRF2 knockdown enhanced the sensitivity of AML cells to the ferroptosis inducers. Taken together, our results suggest that combination therapy targeting both NRF2 and GPX4 may represent a promising approach for the treatment of AML.

Comments:

Your research findings are highly significant in the context of acute myeloid leukemia (AML) and its treatment. Drug resistance and poor treatment response are indeed major challenges in managing AML, necessitating a deeper understanding of the underlying mechanisms. Your study focuses on nuclear factor E2-related factor 2 (NRF2) and its role in AML, particularly its involvement in detoxifying reactive oxygen species and influencing chemotherapy sensitivity.

In your research, you identify a core set of direct NRF2 targets that are associated with ferroptosis, a novel form of cell death. Notably, you find that glutathione peroxidase 4 (GPX4) is a crucial ferroptosis gene consistently upregulated in AML. Moreover, high expression of GPX4 correlates with a poor prognosis for AML patients, highlighting its potential as a therapeutic target.

Importantly, you demonstrate that simultaneous inhibition of NRF2 using ML385 and GPX4 using FIN56 or RSL3 leads to synergistic targeting of AML cells, ultimately triggering ferroptosis. Treatment with ML385 + FIN56/RSL3 effectively reduces the expression of NRF2 and GPX4. Additionally, your research shows that NRF2 knockdown enhances the sensitivity of AML cells to ferroptosis inducers.

Based on these findings, your study suggests that combination therapy targeting both NRF2 and GPX4 holds promise for the treatment of AML. This approach offers a potential solution to overcome drug resistance and improve treatment response in AML patients. By simultaneously inhibiting NRF2 and GPX4, you can exploit the induction of ferroptosis as a therapeutic strategy in AML.

Overall, your research provides valuable insights into the mechanisms underlying drug resistance and treatment response in AML. The identification of NRF2 and GPX4 as critical players in ferroptosis and their association with AML prognosis opens up new avenues for developing effective combination therapies for AML patients.