ArticleOncotarget2016
Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.bioRxiv : the preprint server for biology · 2025Article
- Disarib, a Specific BCL2 Inhibitor, Induces Apoptosis in Triple-Negative Breast Cancer Cells and Impedes Tumour Progression in Xenografts by Altering Mitochondria-Associated Processes.International journal of molecular sciences · 2024Article
- Research Progress on the Use of Metformin in Leukemia Treatment.Current treatment options in oncology · 2024Review
- Mitochondrial transfer in hematological malignancies.Biomarker research · 2023Review
- Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.Biomolecules · 2023Review
- Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Inhibition of Phosphoglycerate Dehydrogenase Radiosensitizes Human Colorectal Cancer Cells under Hypoxic Conditions.Cancers · 2022Article
- Phenformin increases early hematopoietic progenitors in the Jak2Investigational new drugs · 2022Article
- Novel Mango Ginger Bioactive (2,4,6-Trihydroxy-3,5-diprenyldihydrochalcone) Inhibits Mitochondrial Metabolism in Combination with Avocatin B.ACS omega · 2022Article
- Mitochondrial Inhibition: a Treatment Strategy in Cancer?Current oncology reports · 2021Review
- Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia.Journal of Cancer · 2021Article
- From old to new - Repurposing drugs to target mitochondrial energy metabolism in cancer.Seminars in cell & developmental biology · 2020Review
- The Metabolic Profiles in Hematological Malignancies.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2019Review
- Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies.Antioxidants (Basel, Switzerland) · 2019Review
- Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells.Cancers · 2019Review
- Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence.International journal of hematology · 2018Review
- Mitochondria in cancer metabolism, an organelle whose time has come?Biochimica et biophysica acta. Reviews on cancer · 2018Review
- Article
- Metformin exerts multitarget antileukemia activity in JAK2Cell death & disease · 2018Article
- Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption.Frontiers in pharmacology · 2018Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
Abstract
Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.
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