Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL

Yosifov, Deyan Yordanov; Idler, Irina; Bhattacharya, Nupur; Reichenzeller, Michaela; Close, Viola; Ezeriņa, Daria; Scheffold, Annika; Jebaraj, Billy Michael Chelliah; Kugler, Sabrina J.; Bloehdorn, Johannes; Bahlo, Jasmin; Robrecht, Sandra; Eichhorst, Barbara; Fischer, Kirsten; Weigel, Anja; Busch, Hauke; Lichter, Peter; Döhner, Hartmut; Dick, Tobias P.; Stilgenbauer, Stephan; Mertens, Daniel

doi:10.1038/s41375-019-0513-x

Cited by 27 publications

(34 citation statements)

References 47 publications

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“…Several drugs with anti-cancer properties reported for solid tumors including, Mefloquine in glioblastoma [47], Digitoxigenin in renal carcinoma [48] and Emetine in bladder cancer [49] were associated with the Hoxa del signature. Furthermore, some of these drugs e.g., Emetine and Cephaline were recently shown to be highly active against primary chronic lymphocytic leukemia cells by repressing HIF-1α and disturbing intracellular redox homeostasis [50].…”

Section: Discussionmentioning

confidence: 99%

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Kettyle

Lebert-Ghali

Grishagin

et al. 2019

Cancers

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High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.

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Section: Discussionmentioning

confidence: 99%

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Kettyle

Lebert-Ghali

Grishagin

et al. 2019

Cancers

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“…As in other cancer cells, CLL cells must adapt to their increased metabolic demands by boosting their mitochondrial activity and enhancing mitochondrial biogenesis, resulting in oxidative stress through the sustained generation of ROS [28,29,63]. Oxidative stress in CLL cells has thus far not been shown to affect either kinase or phosphatase activities.…”

Section: Cll Cells Exhibit High Ros-buffering Capacity To Preserve Sumentioning

confidence: 99%

“…A few small molecules have been tested in vitro and in vivo, proving effective in eliciting apoptosis of CLL cells not only by subverting their antioxidant machinery but also interfering with the protective role of the micro-environment. For instance, the cardiac glycoside ouabain and the ipecac alkaloid emetine perturb intracellular redox homeostasis in the low nanomolar range by repressing HIF-1α, resulting in a dramatic rise of ROS and apoptosis of CLL cells [29]. The HIF-1α selective inhibitor BAY87-2243 has been shown to exert cytotoxic effects on CLL cells as such and to strongly synergize with the BTK inhibitor inbrutinib or fludarabine, offering new prospects in terms of translational impact.…”

Section: Potentiation Of Antioxidant Defense Systems and Cllmentioning

confidence: 99%

“…These are triggered by B cell receptor (BCR) signaling together with the activation of NF-kB [25][26][27]. Intriguingly, ROS are abundantly produced in CLL cells mainly by mitochondria [28,29]. However, the elevated oxidative potential is counteracted by a marked ROS-buffering capacity provided by both antioxidant enzymes and the support of the microenvironment in lymphoid tissues [28,29].…”

Section: Introductionmentioning

confidence: 99%

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Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

et al. 2020

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The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders.

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“…Further evidence for stroma-induced activation of HIF-1α in CLL comes from a comparative transcriptome analysis of primary CLL cells co-cultured or not with protective BM stromal cells which revealed that oxidative phosphorylation, mitochondrial function and hypoxic signaling are the most significantly deregulated functions in non-protected CLL cells. 10 These relevant transcriptomic changes were compared to the Connectivity Map database, 11 which contains transcriptomic responses of cell lines to treatment with small molecules. This comparison identified drugs that act by repressing HIF-1α and disturbing intracellular redox homeostasis as potential compounds blocking stroma-mediated support of CLL cells.…”

mentioning

confidence: 99%

HIF-1α: a potential treatment target in chronic lymphocytic leukemia

Seiffert

2020

Haematologica

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Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL

Cited by 27 publications

References 47 publications

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

HIF-1α: a potential treatment target in chronic lymphocytic leukemia

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