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

PROVIDER: PRJNA680043 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13106644_1.fastq.gz	Fastqsanger.gz
	SRR13106644_2.fastq.gz	Fastqsanger.gz
	SRR13106645_1.fastq.gz	Fastqsanger.gz
	SRR13106645_2.fastq.gz	Fastqsanger.gz
	SRR13106646_1.fastq.gz	Fastqsanger.gz

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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

Project description: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.

2021-02-26 | GSE161959 | GEO

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

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

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

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

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Genome-scale DNA methylation profiling of TEL/AML positive childhood acute lymphoblastic leukaemia

Project description:DNA methylation profiling of 48 samples to determine a DNA methylation signature specific to leukaemic bone marrow samples. Matching Leukaemia bone marrow and day 28 remission bone marrow or post induction follow up (follow up up to 2 years post induction) genomic DNA were extracted from archived microscope smear slides from 11 children diagnosed with TEL/AML positive Acute Lymphoblastic Leukaemia (ALL). Unmatched bone marrow samples from an additional 8 children were also analysed. Primary tissue control samples from CD34+ and CD19+ bone marrow from adult and childhood samples as well as model cell lines (cancer and non cancerous) were compared to primary diseased samples. Disease specific DNA methylation changes were identified from these results and then verified using SEQUENOM EpiTYPER.

2012-12-31 | GSE29189 | GEO

Genome-scale DNA methylation profiling of TEL/AML positive childhood acute lymphoblastic leukaemia

2012-12-31 | E-GEOD-29189 | biostudies-arrayexpress

WAS enhance organohalides respiration

Project description:WAS enhance organohalides respiration

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Differentiation mutants in the protozoan parasite Toxoplasma gondii.

Project description:Two forms of the protozoan parasite Toxoplasma gondii are associated with intermediate hosts such as humans: rapidly growing tachyzoites are responsible for acute illness, whereas slowly dividing encysted bradyzoites can remain latent within the tissues for the life of the host. In order to identify genetic factors associated with parasite differentiation, we have used a strong bradyzoite-specific promoter (identified by promoter trapping) to drive the expression of T. gondii hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) in stable transgenic parasites, providing a stage-specific positive/negative selectable marker. Insertional mutagenesis has been carried out on this parental line, followed by bradyzoite induction in vitro and selection in 6-thioxanthine to identify misregulation mutants. Two different mutants fail to induce the HXGPRT gene efficiently during bradyzoite differentiation. These mutants are also defective in other aspects of differentiation: they replicate well under bradyzoite growth conditions, lysing the host cell monolayer as effectively as tachyzoites. Expression of the major bradyzoite antigen BAG1 is reduced, and staining with Dolichos biflorus lectin shows reduced cyst wall formation. Microarray hybridizations show that these mutants behave more like tachyzoites at a global level, even under bradyzoite differentiation conditions. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. User Defined

2005-08-13 | E-GEOD-3119 | biostudies-arrayexpress

Differentiation mutants in the protozoan parasite Toxoplasma gondii.

2005-08-13 | GSE3119 | GEO

Protozoan-Derived Cytokine-Transgenic Macrophages Reverse Hepatic Fibrosis.

Project description:Protozoan-Derived Cytokine-Transgenic Macrophages Reverse Hepatic Fibrosis.

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