Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Panina, Svetlana; Pei, Jingqi; Kirienko, Natalia V.

doi:10.1186/s40170-021-00253-w

Cited by 41 publications

(44 citation statements)

References 292 publications

(263 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Excellent reviews reported different approaches to modify ROS levels with an anti-leukemia purpose: lowering the ROS level to prevent their role in cellular transformation or counteracting the redox adaptation by inducing oxidative stress with elevated ROS levels [ 115 , 116 ].…”

Section: The Stromal-dependent Metabolic Reprogrammingmentioning

confidence: 99%

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Ciciarello

Corradi

Forte

et al. 2021

Cancers

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset and progression has been pointed out. In particular, mesenchymal stromal cells (MSCs) steadily remodel the leukemic niche, not only favoring leukemic cell growth and development but also tuning their responsiveness to treatments. The list of mechanisms driven by MSCs to promote a leukemia drug-resistant phenotype has progressively expanded. Moreover, the relative proportion and the activation status of immune cells in the BM leukemic microenvironment may vary by influencing their reactivity against leukemic cells. In that, the capacity of the stroma to re-program immune cells, thus promoting and/or hampering therapeutic efficacy, is emerging as a crucial aspect in AML biology, adding an extra layer of complexity. Current treatments for AML have mainly focused on eradicating leukemia cells, with little consideration for the leukemia-damaged BM niche. Increasing evidence on the contribution of stromal and immune cells in response to therapy underscores the need to hold the mutual interplay, which takes place in the BM. A careful dissection of these interactions will help provide novel applications for drugs already under experimentation and open a wide array of opportunities for new drug discovery.

show abstract

Section: The Stromal-dependent Metabolic Reprogrammingmentioning

confidence: 99%

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Ciciarello

Corradi

Forte

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…However, we observed an increase in both glycolysis and OXPHOS. As AML cells heavily rely on OXPHOS for cell survival and were shown to be particularly sensitive to mitochondria damaging agents [ 73 , 74 , 75 , 76 ], we observed increased sensitivity of ATG3-deficient AML cells to OXPHOS inhibiting drugs oligomycin and antimycin A whereas ATG3-depleted AML cells were resistant glycolysis inhibition ( Figure 5 C). A recent study has demonstrated that AML cell lines differ in their energy metabolism.…”

Section: Discussionmentioning

confidence: 87%

“…This indicates that the dependency of AML cells shifts towards OXPHOS with deficient autophagy. Furthermore, targeting mitochondria is used as potential therapeutic target in combat against cancer [ 40 , 78 , 79 ] and the combination treatment of hydroxychloroquine together with mitoxantrone and etoposide (mitochondrial DNA inhibitors by topoisomerase II) is already in phase I clinical trials [ 76 ]. Besides that, Bhattacharya et al reported the potential of using SBI-0206965, an autophagy inhibitor, combined with venetoclax in AML treatment [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3

Baker

Polat

Abou-El-Ardat

et al. 2021

Cancers

View full text Add to dashboard Cite

Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.

show abstract

“…The oxidative stress-inducing effect of EANT was validated by the evidence of ROS, MitoSOX, and MMP flow cytometry in leukemia HL-60 cells ( Figure 5 , Figure 6 and Figure 7 ). Moreover, mitochondrial metabolism is a vital target for AML therapy [ 59 ]. Targeting mitochondria for ROS and MitoSOX modulations can improve the therapeutic effects of AML [ 23 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects

et al. 2021

View full text Add to dashboard Cite

Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.

show abstract

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Cited by 41 publications

References 292 publications

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3

Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects

Contact Info

Product

Resources

About