Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia

Abstract

Pediatric acute myeloid leukemia (AML) represents 20% of total childhood leukemia diagnoses and is characterized by poor prognosis with a long-term survival rate around the 50%, when patients are properly treated. The standard treatment for pediatric AML currently consists in a combination of cytarabine (Ara-C) and antracycline. Iron plays an important role in cancer development and progression. Targeting iron and its metabolism mediators could be a novel therapeutic strategy in cancer.Deferasirox (DFX) inhibits cancer cell proliferation and its use as an antiblastic drug could be suggested. Eltrombopag (ELT), a thrombopoietin receptor agonist used in immunethrombocytopenia, shows anticancer properties related to its emerging iron chelating properties. We compare the anticancer effect of classically used cytarabine with DFX and ELT effects in a pediatric AML cell line, THP-1, in order to identify innovative and more effective therapeutic strategies. ELT and DFX reduce intracellular iron concentration by inhibiting its uptake and by promoting its release.In particular, even though further investigations are needed to better understand the extact underlying action mechanisms, we demonstrated that ELT improves cytarabine antineoplastic activity in pediatric AML cell line.

Emerging Roles of the Iron Chelators in Inflammation

“…In recent years, it has been proved that ELT is also able to bind the main intracellular iron form Fe 3+ , showing iron chelating properties [ 71 , 96 , 101 , 103 , 107 , 108 ]. In particular, in 2017 Vlachodimitropoulou et al demonstrated in both human hepatoma cells (HuH7) and rat cardiomyocytes (H9C2) that ELT is a powerful iron chelator responsible for intracellular iron concentration reduction and iron mobilization when it was combined with other chelators, through a shuttling mechanism [ 108 ].…”

Exploring the Potential of Eltrombopag: Room for More?

“…Notably, robust evidence supports ELT iron chelation properties that could ameliorate the fitness of HSCs and hematopoiesis, especially considering that SAA patients are frequently transfusion-dependent ( Vlachodimitropoulou et al, 2017 ; Zhao et al, 2018 ). Moreover, the ELT-mediated mobilization of intracellular iron and the decrease of serum ferritin levels observed in various clinical contexts ( Roth et al, 2012 ; Vlachodimitropoulou et al, 2017 ; Punzo et al, 2018 ; Zhao et al, 2018 ; Argenziano et al, 2021 ) could help to prevent long-term multi-organ complications and improve BM function.…”

“…Moreover, preliminary studies aiming to evaluate ELT efficacy and safety in the context of MDS and AML did not show increased blast proliferation or clonogenic properties, while confirming the improvement in platelets counts ( Will et al, 2009 ; Mavroudi et al, 2011 ). Furthermore, ELT showed antileukemic effects related to its iron chelation properties, the capacity to activate pro-apoptotic signaling through reactive oxygen species (ROS) modulation and induce cellular differentiation ( Roth et al, 2012 ; Kalota et al, 2015 ; Argenziano et al, 2021 ). Against this background, results from MDS and AML trials confirm ELT effectiveness in treating hypoplastic and low to intermediate-1 risk MDS, while data from higher-risk MDS and AML are conflicting and affected by the rates of clonal evolution and disease progression ( Buckstein, 2015 ; Mittelman et al, 2018 ; Frey et al, 2019 ; Vicente et al, 2020 ).…”

“…Moreover, ELT has proven efficacy in myelodysplastic syndrome (MDS) and the therapy of post-transplant poor graft function (PGF) ( Tang et al, 2018 ; Vicente et al, 2020 ), while data in the context of acute myeloid leukemia (AML) are conflicting ( Buckstein, 2015 ; Mittelman et al, 2018 ; Frey et al, 2019 ; Shi et al, 2019 ). ELT can decrease cellular iron and enhance its mobilization in combination with available chelators, thus reducing reactive oxygen species (ROS) levels and improving cellular fitness in various clinical contexts ( Roth et al, 2012 ; Vlachodimitropoulou et al, 2017 ; Argenziano et al, 2021 ).…”

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

“…The pharmacological effect of EPAG interactions with TPO-R results in an increase of differentiation and proliferation rate of the megakaryocytoblastic cellular line and its precursors. Alongside this effect on platelet count, recent evidence also suggests an immune-modulating and iron chelating property of EPAG ( Argenziano et al, 2021 ; Di Paola et al, 2021 ).…”