Targeting the mitochondria in acute myeloid leukemia

Sánchez-Mendoza, Silvia Elena; Rego, Eduardo Magalhães

doi:10.1186/s41241-017-0022-z

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…Hexokinase II, the most common version of the enzyme in insulin-sensitive tissues, is a key player in controlling metabolic flux through this pathway. Unsurprisingly, it is also frequently upregulated in cancer cells (reviewed in [ 30 , 31 ]). One potential method to target hexokinase is to use 3-bromopyruvic acid or 2-deoxy- d -glucose (2-DG), both of which inhibit glucose metabolism [ 32 , 33 ].…”

Section: Glycolytic Disruptions In Aml Blasts and Lscsmentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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Acute myeloid leukemias (AML) are a group of aggressive hematologic malignancies resulting from acquired genetic mutations in hematopoietic stem cells that affect patients of all ages. Despite decades of research, standard chemotherapy still remains ineffective for some AML subtypes and is often inappropriate for older patients or those with comorbidities. Recently, a number of studies have identified unique mitochondrial alterations that lead to metabolic vulnerabilities in AML cells that may present viable treatment targets. These include mtDNA, dependency on oxidative phosphorylation, mitochondrial metabolism, and pro-survival signaling, as well as reactive oxygen species generation and mitochondrial dynamics. Moreover, some mitochondria-targeting chemotherapeutics and their combinations with other compounds have been FDA-approved for AML treatment. Here, we review recent studies that illuminate the effects of drugs and synergistic drug combinations that target diverse biomolecules and metabolic pathways related to mitochondria and their promise in experimental studies, clinical trials, and existing chemotherapeutic regimens.

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Section: Glycolytic Disruptions In Aml Blasts and Lscsmentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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“…Tumor cells exhibit a range of metabolic adaptations, including aberrant mitochondrial metabolism, abnormal expression of metabolic enzymes, and increased dependence on glycolysis for ATP generation 1,2 . They also frequently exhibit dysregulation in other mitochondrial parameters, including deregulated mtDNA content, increased ROS production, and defects in oxidative phosphorylation, suggesting that these alterations can be indicative of carcinogenesis 3–5 .…”

Section: Introductionmentioning

confidence: 99%

A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs

et al. 2019

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Mitochondria play a central and multifunctional role in the progression of tumorigenesis. Although many recent studies have demonstrated correlations between mitochondrial function and genetic makeup or originating tissue, it remains unclear why some cancers are more susceptible to mitocans (anticancer drugs that target mitochondrial function to mediate part or all of their effect). Moreover, fundamental questions of efficacy and mechanism of action in various tumor types stubbornly remain. Here we demonstrate that cancer type is a significant predictor of tumor response to mitocan treatment, and that acute myeloid leukemias (AML) show an increased sensitivity to these drugs. We determined that AML cells display particular defects in mitochondrial metabolism that underlie their sensitivity to mitocan treatment. Furthermore, we demonstrated that combinatorial treatment with a mitocan (CCCP) and a glycolytic inhibitor (2-deoxyglucose) has substantial synergy in AML cells, including primary cells from patients with AML. Our results show that mitocans, either alone or in combination with a glycolytic inhibitor, display anti-leukemia effects in doses much lower than needed to induce toxicity against normal blood cells, indicating that mitochondria may be an effective and selective therapeutic target.

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“…They can do this not only through increased dependence on glycolysis, the Warburg effect, but also can modify mitochondria through induction of changes to mitochondrial DNA (mtDNA), increased reactive oxygen species (ROS) production, and changes in oxidative phosphorylation (OXPHOS). 183,184 As there is a greater understanding about the dynamic role that mitochondria play in cancer cell survival and persistence, the development of therapeutics to target mitochondria (mitocans) has been of increasing interest. 183 There are a diverse amount of pathways that can be targeted to impact mitochondria, including apoptosis (Bcl-2 family proteins), enzymatic pathways [tricarboxylic acid (TCA) cycle, glutaminolysis, fatty acid synthesis, etc.…”

Section: Mitochondria Pathway Targetsmentioning

confidence: 99%

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

Carter

Hege

Yang

et al. 2020

Sig Transduct Target Ther

140

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Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

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Targeting the mitochondria in acute myeloid leukemia

Cited by 16 publications

References 38 publications

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

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