ArticleBlood advances2019
Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The trial behind it
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Who cites it
36 citing papers in PubMed, 59 citations in OpenAlex.
- Exploiting Metabolic Vulnerabilities in Acute Myeloid Leukemia: Rationale and Evidence for Combining Metabolic Modulators with Conventional Chemotherapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Review
- Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.Cell death & disease · 2026Article
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- The oxidative phosphorylation inhibitor, atovaquone, upregulates PD-L1 via activation of the ATM/ATR DNA damage response pathway.Research square · 2026Article
- DeepTarget predicts anti-cancer mechanisms of action of small molecules by integrating drug and genetic screens.NPJ precision oncology · 2025Article
- Characterization of Chemoresistant Cell Populations Improves Risk Stratification and Therapy Prediction in Pediatric AML.bioRxiv : the preprint server for biology · 2025Article
- Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.Science advances · 2025Article
- Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.Cancers · 2025Review
- Atovaquone-induced activation of the PERK/eIF2α signaling axis mitigates metabolic radiosensitisation.Cell communication and signaling : CCS · 2025Article
- STAT signaling in the pathogenesis and therapy of acute myeloid leukemia and myelodysplastic syndromes.Neoplasia (New York, N.Y.) · 2025Review
- Current Knowledge of the Integrated Stress Response in the Development and Management of Acute Myeloid Leukemia: A Novel Target with Encouraging Progress.Drug design, development and therapy · 2025Review
- Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.Current pharmacology reports · 2024Article
- Glutathione‑degrading enzymes in the complex landscape of tumors (Review).International journal of oncology · 2024Review
- Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.Cancers · 2024Review
- Liquid Chromatography-Tandem Mass Spectrometry-Based Therapeutic Monitoring of Plasma Atovaquone Concentrations in Pediatric Patients.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy.Open medicine (Warsaw, Poland) · 2024Article
- A Review of Childhood Acute Myeloid Leukemia: Diagnosis and Novel Treatment.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Crosstalk between oxidative phosphorylation and immune escape in cancer: a new concept of therapeutic targets selection.Cellular oncology (Dordrecht, Netherlands) · 2023Review
- Article
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 3 countries.
Funding
Abstract
Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.