Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

Waters, Torin; Goss, Kelli L.; Koppenhafer, Stacia L.; Terry, William W.; Gordon, David

doi:10.1186/s12885-020-07668-6

Cited by 12 publications

(12 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of EP in stimulating hematopoiesis in bone marrow failure has been clinically validated. 1,4,5,11,25,26 Nevertheless, besides the well-known direct actions of this drug on hematopoietic progenitor cells, our study helps show how EP exerts some interesting effects on the stromal compartment that can also favor the hematopoietic process. 2 We have shown here for the first time how EP can act on MSCs, increasing their proliferation and osteogenic differentiation capacity while decreasing their adipogenic differentiation ability.…”

Section: Discussionmentioning

confidence: 87%

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells

Muntión

Preciado

Sánchez-Luis

et al. 2022

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Background: Eltrombopag (EP) is a small molecule that acts directly on hematopoietic stem cells (HSCs) and megakaryocytes to stimulate the hematopoietic process. Mesenchymal stem/stromal cells (MSCs) are key hematopoietic niche regulators. Objectives: We aimed to determine whether EP has any effect on MSC function and properties (especially on their hematopoietic-supporting ability) and if so, what changes (e.g. genome-wide transcriptomic alterations) are induced in MSC after EP treatment. Design/Methods: MSCs were isolated from 12 healthy donors and treated with 15 µM and 50 µM of EP for 24 h. The toxicity of the drug on MSCs and their differentiation ability were analyzed, as well as the transcriptomic profile, reactive oxygen species (ROS) and DNA damage and the changes induced in the clonogenic capacity of HSCs. Results: The results show that EP also modifies MSC functions, decreasing their adipogenic differentiation, increasing the expression of genes involved in hypoxia and other pathways related to oxygen homeostasis, and enhancing their ability to support hematopoiesis in vitro. Conclusion: Our findings support the use of EP in cases where hematopoiesis is defective, despite its well-known direct effects on hematopoietic cells. Our findings suggest that further studies on the effects of EP on MSCs from patients with aplastic anemia are warranted.

show abstract

Section: Discussionmentioning

confidence: 87%

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells

Muntión

Preciado

Sánchez-Luis

et al. 2022

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

show abstract

“…In previous work, we used reverse phase protein arrays to identify that HHT reduces the levels of many proteins in Ewing sarcoma cell lines, including ribonucleotide reductase M2 (RRM2) ( 47 ). RRM2 is a subunit of ribonucleotide reductase (RNR), which is the rate limiting enzyme in the synthesis of deoxyribonucleotides, and a therapeutic target in Ewing sarcoma tumors ( 47 , 48 , 60 – 62 ). Overexpression of ID2 in TC71 cells partially rescued the effects of HHT on the level of ID2, but did not impact the effect of HHT on the level of RRM2 or the sensitivity of the cells to HHT ( Supplementary Figure 11A – B ).…”

Section: Resultsmentioning

confidence: 99%

Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma

et al. 2022

Self Cite

View full text Add to dashboard Cite

Sarcomas are difficult to treat and the therapy, even when effective, is associated with long-term and life-threatening side effects. In addition, the treatment regimens for many sarcomas, including Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, are relatively unchanged over the past two decades, indicating a critical lack of progress. Although differentiation-based therapies are used for the treatment of some cancers, the application of this approach to sarcomas has proven challenging. Here, using a CRISPR-mediated gene knockout approach, we show that Inhibitor of DNA Binding 2 (ID2) is a critical regulator of developmental-related genes and tumor growth in vitro and in vivo in Ewing sarcoma tumors. We also identified that homoharringtonine, which is an inhibitor of protein translation and FDA-approved for the treatment of leukemia, decreases the level of the ID2 protein and significantly reduces tumor growth and prolongs mouse survival in an Ewing sarcoma xenograft model. Furthermore, in addition to targeting ID2, homoharringtonine also reduces the protein levels of ID1 and ID3, which are additional members of the ID family of proteins with well-described roles in tumorigenesis, in multiple types of cancer. Overall, these results provide insight into developmental regulation in Ewing sarcoma tumors and identify a novel, therapeutic approach to target the ID family of proteins using an FDA-approved drug.

show abstract

“…These properties seem to mediate the newly investigated anti-tumor properties of ELT. It is reported that it induces anti-proliferative and pro-apoptotic effects in leukemia cells by binding labile iron and reducing its intracellular concentration [ 109 , 110 , 111 ]. Argenziano et al suggested a possible synergism between ELT and cytarabine in pediatric acute myeloid leukemia (AML) cell line (THP1), observing an increase of cancer cell apoptosis, a decrease of their viability and proliferation, and also an arrest of cell cycle progression when drugs were co-administered.…”

Section: Eltrombopag As An Anti-inflammatory Moleculementioning

confidence: 99%

“…These effects were probably due to iron chelating properties of ELT [ 107 ]. Anti-cancer effects of ELT mediated by its iron chelating properties are reported also in other cancers, among them Ewing sarcoma tumors [ 111 ], hepatocellular carcinoma [ 112 ].…”

Section: Eltrombopag As An Anti-inflammatory Moleculementioning

confidence: 99%

Emerging Roles of the Iron Chelators in Inflammation

Paola

Tortora

Argenziano

et al. 2022

IJMS

View full text Add to dashboard Cite

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

show abstract

Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

Cited by 12 publications

References 56 publications

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells

Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma

Emerging Roles of the Iron Chelators in Inflammation

Contact Info

Product

Resources

About