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The protozoan inhibitor Atovaquone affects mitochondrial respiration and shows in vitro efficacy against glucocorticoid-resistant cells in childhood B-cell acute lymphoblastic leukaemia

ABSTRACT: Atovaquone is a well-tolerated drug used in the clinic mainly against malaria. Being a ubiquinone analogue, this drug inhibits co-enzyme Q10 of the electron transport chain (ETC) affecting oxidative phosphorylation and cell metabolism. In this study we tested the effect of Atovaquone on cALL cells in vitro. The outcome of this inhibition of the ETC is a marked decrease in basal respiration and ATP levels, as well as reduced proliferation, cell cycle arrest and induction of apoptosis. On the transcriptional level, we see changes in cellular metabolic processes, activation of p53 pathway, apoptosis, enrichment of cell cycles genes and downregulation of hypoxia and mTORC1 signalling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161959 | GEO | 2021/02/26

REPOSITORIES: GEO

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The Protozoan Inhibitor Atovaquone Affects Mitochondrial Respiration and Shows <i>In Vitro</i> Efficacy Against Glucocorticoid-Resistant Cells in Childhood B-Cell Acute Lymphoblastic Leukaemia.

Project description:Childhood acute lymphoblastic leukaemia (cALL) accounts for about one third of all paediatric malignancies making it the most common cancer in children. Alterations in tumour cell metabolism were first described nearly a century ago and have been acknowledged as one of the key characteristics of cancers including cALL. Two of the backbone chemotherapeutic agents in the treatment of this disease, Glucocorticoids and L-asparaginase, are exerting their anti-leukaemic effects through targeting cell metabolism. Even though risk stratification and treatment regimens have improved cure rates to nearly 90%, prognosis for relapsed children remains poor. Therefore, new therapeutic approaches are urgently required. Atovaquone is a well-tolerated drug used in the clinic mainly against malaria. Being a ubiquinone analogue, this drug inhibits co-enzyme Q10 of the electron transport chain (ETC) affecting oxidative phosphorylation and cell metabolism. In this study we tested the effect of Atovaquone on cALL cells in vitro. Pharmacologically relevant concentrations of the inhibitor could effectively target mitochondrial respiration in both cALL cell lines (REH and Sup-B15) and primary patient samples. We found that Atovaquone leads to a marked decrease in basal respiration and ATP levels, as well as reduced proliferation, cell cycle arrest, and induction of apoptosis. Importantly, we observed an enhanced anti-leukaemic effect when Atovaquone was combined with the standard chemotherapeutic Idarubicin, or with Prednisolone in an in vitro model of Glucocorticoid resistance. Repurposing of this clinically approved inhibitor renders further investigations, but also presents opportunities for fast-track trials as a single agent or in combination with standard chemotherapeutics.

| S-EPMC8005808 | biostudies-literature

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Identification of LPS-inducible genes down-regulated by ubiquinone in human THP-1 cells

Project description:Coenzyme Q10 (CoQ10) is an obligatory element in the respiratory chain and functions as a potent antioxidant of lipid membranes. More recently, anti-inflammatory effects as well as an impact of CoQ10 on gene expression have been observed. To reveal putative effects of Q10 on LPS-induced gene expression, whole genome expression analysis was performed in the monocytic cell line THP-1. 1129 probe sets have been identified to be significantly up-regulated (p < 0.05) in LPS-treated cells when compared to controls. Text mining analysis of the top 50 LPS up-regulated genes revealed a functional connection in the NFκB pathway and confirmed our applied in vitro stimulation model. Moreover, 33 LPS-sensitive genes have been identified to be significantly down-regulated by Q10-treatment between a factor of 1.32 and 1.85. GeneOntology (GO) analysis revealed for the Q10-sensitve genes a primary involvement in protein metabolism, cell proliferation and transcriptional processes. Three genes were either related to NFκB transcription factor activity, cytokinesis or modulation of oxidative stress. In conclusion, our data provide evidence that Q10 down-regulates LPS-inducible genes in the monocytic cell line THP-1. Thus, the previously described effects of Q10 on the reduction of pro-inflammatory mediators might be due to its impact on gene expression. Whole genome expression profiles were analysed from monocytes pre-incubated with ubiquinone (Q10) before subsequent stimulation with LPS. Stimulated (+LPS) and unstimulated (-LPS) monocytes were used as positive and negative controls, respectively. For every experimental group (3 groups in total), three Affymetrix Human Genome U133 Plus 2.0 arrays were used, thus resulting in the analysis of 9 microarrays.

2010-12-22 | E-GEOD-19625 | biostudies-arrayexpress

The mevalonate pathway is required for pyrimidine synthesis and survival of p53-deficient colon cancer cells in metabolically compromised environments

Project description:In this study, we have investigated the effect of p53 deletion on the metabolic activity of colon cancer cells exposed to metabolic stress. In order to recreate the simultaneous reduction in oxygen and nutrient availability found in tumors, we cultured cancer cells as multicellular tumor spheroids. Under these conditions, p53 deficient cancer cells activate the expression of enzymes of the mevalonate pathway via the sterol regulatory element binding protein 2 (SREBP2). Moreover, inhibition of mevalonate pathway activity with statins selectively induced apoptosis in p53 deficient cancer cells exposed to metabolic stress. This effect was mediated by the requirement of p53 deficient cancer cells to synthesise ubiquinone (coenzyme Q10) to maintain TCA cycle activity, respiration and the production of pyrimidine nucleotides. Our study has revealed a novel link between isoprenoid synthesis by the mevalonate pathway and the electron transport function of ubiquinone, which is required for nucleotide biosynthesis. As a consequence, maintaining mevalonate pathway activity is essential for p53 deficient cancer cells to proliferate and survive under the metabolic constraints of the tumor microenvironment.

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Project description:Ubiquinone (UQ), also known as “coenzyme Q” is an essential player in the mitochondrial respiratory electron transport chain as well as a lipid-soluble antioxidant in eukaryotic cells. In this study, we attempted to identify the proteins involved in the pathway by which the exogenous UQ is taken up and accumulated in mitochondria through chemical biology approaches. This project contains MS and MS/MS analysis of the proteins which were specifically labeled by the photo-reactive ubiquinone analogue.

2024-06-25 | PXD049194 | JPOST Repository

The protozoan inhibitor Atovaquone affects mitochondrial respiration and shows in vitro efficacy against glucocorticoid-resistant cells in childhood B-cell acute lymphoblastic leukaemia

Project description:The protozoan inhibitor Atovaquone affects mitochondrial respiration and shows in vitro efficacy against glucocorticoid-resistant cells in childhood B-cell acute lymphoblastic leukaemia

| PRJNA680043 | ENA

Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

Project description:To identify novel therapeutic targets in Acute Myeloid Leukemia (AML), we chemically interrogated 200 sequenced primary specimens. We identified Mubritinib, a known ERBB2 inhibitor, as a strong in vitro and in vivo anti-leukemic compound. We demonstrate that, in the context of AML, Mubritinib functions through ubiquinone-dependent inhibition of Electron Transport Chain (ETC) complex I activity. Resistance to Mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies a novel ETC complex I inhibitor and reveals for the first time the genetic landscape of OXPHOS dependency in this disease.

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Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells

Project description:In spite of the considerable progress in risk stratification and therapeutic regimens in childhood acute lymphoblastic leukaemia (cALL), which has led to cure rates of above 90%, prognosis for patients with relapsed disease remains poor. The main cause of therapy failure is drug resistance, most commonly to glucocorticoids (GCs). While alterations of cell metabolism in cALL are considered a hallmark of this malignancy as well, the molecular differences between prednisolone sensitive and resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to investigate the biology of matched pairs of cell lines where GCs are effective and such with acquired lack of response to prednisolone. In order to address this, we took advantage of the molecular characterisation of an in vitro model of GC resistance we had previously developed. An integrated transcriptomic and metabolomic analysis revealed alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signaling, which are also known to control cell metabolism. In attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis in both GC-sensitive and resistant cell lines. In summary, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. We suggest that targeting glutamine metabolism presents a novel therapeutic approach in cALL.

2023-02-19 | GSE217428 | GEO

Transcriptional response in acute lymphoblastic leukaemia cells to bone marrow microenvironment

Project description:Glucocorticoids (GCs) and topoisomerase II inhibitors are used in the treatment of acute lymphoblastic leukaemia (ALL) due to their ability to induce cell death in lymphoid cells. GC-induced apoptosis is mediated by the glucocorticoid receptor (GR), whereas topoisomerase II inhibitors cause DNA damage and activate sensors of DNA damage including the tumour suppressor p53. In order to shed light on the role of the microenvironment in cell death and identify determinants of drug sensitivity we performed transcriptomic analysis in ALL cells treated with the synthetic glucocorticoid dexamethasone, and the topoisomerase II inhibitor etoposide combined with bone marrow-derived conditioned media (CM).

2017-08-30 | E-MTAB-4761 | biostudies-arrayexpress

A stop-and-go mechanism controls mitochondrial respiration

Project description:Oxidative phosphorylation (OXPHOS) is essential for the synthesis of the vast majority of ATP in eukaryotic cells. It is carried out by multi-protein assemblies that form the electron transport chain (ETC), which are coupled to the mitochondrial ATP synthase, which uses the proton gradient generated by the ETC to drive ATP synthesis. The assembly of the OXPHOS protein machinery requires the coordinated integration of proteins encoded in the nuclear and the mitochondrial genomes, imposing an additional layer of complexity. While the biogenesis of the individual OXPHOS complexes is well understood, it remains unknown how the assembly of the ETC and ATP synthase is coordinated to achieve the correct stoichiometry of the OXPHOS machinery. Here, we identify the mitochondrial regulatory hub for respiratory assembly (MiRA), which serves as a platform on which complex IV and complex V biogenesis are synchronised to ensure balanced assembly of the ETC and complex V. At the molecular level, this is achieved by a stop-and-go safeguarding mechanism: The novel mitochondrial protein Mra1 binds to and slows down complex IV assembly. Two Go signals are then required for assembly to proceed: Binding of the complex IV assembly factor Rcf2 and interaction with the mitoribosome, which translates the complex V subunit Atp9. Both Go signals induce the clipping and subsequent degradation of Mra1, relieving the molecular break and allowing parallel maturation of complexes IV and V. The absence of the stop-and-go safety mechanism results in the formation of immature complexes, decreased ATP levels and reduced cell viability. The antagonistic activities at MiRA provide a regulated orchestration of complex IV and V assembly which is essential to avoid the predominance of either complex and an unbalanced ratio of OXPHOS complexes, thus ensuring the correct stoichiometry of protein machineries encoded by two different genomes.

2024-02-16 | PXD044800 | Pride

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