<p>The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells</p>

Abstract

BackgroundHypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined.PurposeTo explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines.MethodsIn our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels.ResultsOur results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death.ConclusionOur study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.

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

“…Instead, we identified that the growth inhibitory effect of eltrombopag is due, in part, to the iron chelation properties of the drug, which provides further support for our previous work that identified iron chelator drugs as a unique vulnerability of Ewing sarcoma tumor in vitro and in vivo [7]. Notably, eltrombopag has also been reported to target additional cancer types, including leukemia and hepatocellular carcinoma, via an iron chelation mechanism [12,13,55].…”

Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia

“…This controversial aspect on iron overload management could depend on the considered cell type and health condition. As regards cell cycle progression, we observed a block in S phase after cytarabine administration in THP-1 cells, as also reported for decitabine, another chemotherapy drug currently used in AML not eligible for standard protocols [37]. But, when we combined it with ELT, the arrest shifted in G0/G1 phase, consistently with the already documented effects of ELT used alone [37,40].…”

“…As regards cell cycle progression, we observed a block in S phase after cytarabine administration in THP-1 cells, as also reported for decitabine, another chemotherapy drug currently used in AML not eligible for standard protocols [37]. But, when we combined it with ELT, the arrest shifted in G0/G1 phase, consistently with the already documented effects of ELT used alone [37,40]. Several authors demonstrated that iron chelators reduce cyclin-dependent kinase 2 (CDK2) activity [41][42][43], a protein normally responsible for cell cycle progression from G0/G1 phase to S one.…”

“…This difference could be due to biological differences between cancers and also to differences in therapy strategies. Even though the role of ferroportin in cancer need to be better clarified, in literature it is clear the potential anticancer role of iron chelation and in particular ELT seems to be a very promising agent in this field [ 36 , 37 ].…”

“…All treatments we administered caused a significative increase in CDK2 expression, which is not in accordance with the arrest actually observed by cytofluorimetry. Therefore, it could be interesting to investigate on the hypothesis formulated by Shi et al ., which observed an arrest in G0/G1 phase after treating leukemia cells with ELT and decitabine [ 37 ] and attributed this anticancer effect to the alteration in intracellular ROS levels caused by ELT [ 40 ]. We also evaluated the effect of treatments on cell proliferation by analyzing the expression levels of nuclear transcription factor-kappa beta (NFkB), one of the principal mediators of inflammation, carcinogenesis [ 45 , 46 ] and chemotherapy resistance [ 38 ].…”