BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells
By E. Lagadinou, Alexander Šach, K. Callahan, R. M. Rossi, S. Neering, Mohammad Minhajuddin, J. Ashton, Shanshan Pei, Valerie Grose, K. O'Dwyer and 4 more. Cell Stem Cell, 2013
1,264 citations recorded by the source corpus.
Summary Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
Subfields: Cancer Research, Hematology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c80c3e01dfbf947c76cb5f05b665110303121676
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In Cancer Research
- C. V. Dang
- B. Altman
- Zachary E. Stine
- G. Semenza
- Ralph J. Deberardinis
- Jason W. Locasale
- Y. Fouad
- C. Aanei
In Molecular Biology
- B. Altman
- Zachary E. Stine
- C. V. Dang
- Ralph J. Deberardinis
- G. Semenza
- Jason W. Locasale
- Y. Fouad
- C. Aanei
Citations in the corpus
- Oxidative Phosphorylation as an Emerging Target in Cancer Therapy (2018, background): “OXPHOS is also enhanced in acute myelogenous leukemia (AML) stem cells, dependent upon expression of the BCL-2 oncogene (27).”
- Chemotherapy Resistant Human Acute Myeloid Leukemia Cells are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism (2017, background): “In Vivo RLCs Have Elevated ROS Levels and Active Mitochondria after AraC Treatment On the basis of the literature (30, 31) and on our transcriptomic signature of RLCs enriched in inflammatory, stress, and ROS responses, we hypothesized that in vivo AraC chemotherapy could induce redox alteration and”
- MYC, Metabolism, and Cancer. (2015, background): “Additional studies to determine whether dormant cancer cells use this previously unsuspected memory T-cell futile cycle may reveal additional metabolic rewiring pathways used by cancer cells (73, 74).”
- HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “ROS levels vary widely in cancer cells, with high ROS levels often associated with cell proliferation (43), whereas low ROS levels have been associated with resistance to chemotherapy (44) and the stem cell phenotype (45, 46).”
- Cuproptosis: mechanisms and links with cancers (2023, background): “Higher levels of mitochondrial respiration were demonstrated in certain drug-resistant tumors treated with chemotherapy by cisplatin [9] or 5-fluorouracil [11] or target therapy by anti-EGFR [12] or anti-BCL-2 [13], which were also thought to be associated with drug resistance.”