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Venetoclax combined with ML385 overcomes chemotherapy resistance in acute myeloid leukemia by modulating
Long Zhao1,2, Yuancheng Guo1,2, Jinli Jian2
1Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
Abstract:
This study aimed to investigate the potential of Venetoclax combined with ML385 to overcome drug resistance in leukemia cells and the related mechanisms. Analysis of Nrf2 expression and its prognostic significance in AML was performed utilizing the GEO and GEPIA2 databases. Bone marrow specimens were collected from newly diagnosed AML patients to evaluate Nrf2 expression levels and assess their correlation with established risk stratification and clinical prognosis. Two doxorubicin-resistant leukemia cell lines were established. Subsequently, stable Nrf2-knockdown cell lines were generated via lentiviral transduction. Cellular proliferation and apoptosis were analyzed. Levels of reactive oxygen species (ROS) and glutathione (GSH), alongside the expression of oxidative stress-related and apoptosis-related genes and proteins, were quantified. Furthermore, the effects of Venetoclax combined with ML385 on proliferation, apoptosis, ROS levels, and GSH levels were subsequently investigated in these doxorubicin-resistant cell lines. Mechanistically, the impact of the drug combination on oxidative stress and the PI3K/AKT signaling pathway was explored. Nrf2 was up-regulated in AML and predicted poor prognosis. In doxorubicin-resistant AML cells, oxidative-stress genes were elevated. Silencing Nrf2 inhibited proliferation, induced apoptosis, lowered GSH, raised ROS, increased pro-apoptotic BAX and Caspase-3, and decreased anti-apoptotic Bcl-2. Combining the venetoclax with ML385 significantly suppressed proliferation and induced apoptosis in drug-resistant leukemia cells. Mechanistically, this dual-targeting regimen concurrently attenuated both the Nrf2-mediated antioxidant defense and the pro-survival PI3K/AKT signaling axis, which collectively underpin its enhanced anti-leukemic efficacy. This study demonstrates venetoclax combined with ML385 overcomes chemotherapy resistance in acute myeloid leukemia by modulating Nrf2/ARE-mediated oxidative stress.These findings reveal a novel mechanism and a promising therapeutic strategy.
Insights
Venetoclax plus ML385 overcomes drug resistance in acute myeloid leukemia (AML) by targeting Nrf2-mediated oxidative stress and PI3K/AKT signaling. This combination therapy offers a promising new strategy for treating resistant leukemia.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) often develops resistance to chemotherapy.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is implicated in drug resistance and oxidative stress in AML.
- Targeting Nrf2 and related pathways presents a potential strategy to overcome chemoresistance.
Purpose of the Study:
- To investigate if Venetoclax combined with ML385 can overcome drug resistance in leukemia cells.
- To elucidate the underlying mechanisms, including Nrf2 expression, oxidative stress, and PI3K/AKT signaling.
- To evaluate the prognostic significance of Nrf2 in AML patients.
Main Methods:
- Analysis of Nrf2 expression in AML patient data (GEO, GEPIA2) and bone marrow specimens.
- Establishment of doxorubicin-resistant leukemia cell lines and Nrf2-knockdown cell lines.
- Assessment of cellular proliferation, apoptosis, reactive oxygen species (ROS), glutathione (GSH), and gene/protein expression.
- Investigation of the effects of Venetoclax plus ML385 on resistant cells and signaling pathways.
Main Results:
- Nrf2 was upregulated in AML and correlated with poor prognosis.
- Doxorubicin-resistant cells showed elevated oxidative stress markers.
- Nrf2 knockdown inhibited proliferation, induced apoptosis, and modulated ROS/GSH levels.
- Venetoclax plus ML385 significantly suppressed proliferation and induced apoptosis in resistant cells.
- The combination therapy attenuated Nrf2-mediated antioxidant defense and PI3K/AKT signaling.
Conclusions:
- Venetoclax combined with ML385 effectively overcomes chemotherapy resistance in acute myeloid leukemia.
- This dual-targeting approach modulates Nrf2/ARE-mediated oxidative stress and PI3K/AKT signaling.
- The findings suggest a novel and promising therapeutic strategy for resistant AML.
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