Deferasirox combination with eltrombopag shows anti-myelodysplastic syndrome effects by enhancing iron deprivation-related apoptosis.

Abstract

Iron overload (IO) affected the survival of patients with myelodysplastic syndrome (MDS). Deferasirox (DFX) is widely used in patients with MDS for iron chelation therapy, but is not suitable for MDS patients with severe thrombocytopenia. Eltrombopag (ELT) is a type of thrombopoietin receptor (TPOR) analog used in the treatment of thrombocytopenia. Therefore, we sought to explore the synergistic effects and possible mechanisms of DFX combination with ELT in MDS cells. In our study, the combination of DFX with ELT synergistically inhibited proliferation, induced apoptosis and arrested cell cycle of MDS cells. Through the RNA-sequence and gene set enrichment analysis (GSEA), iron metabolism-related pathway played important roles in apoptosis of SKM-1 cells treated with DFX plus ELT. Transferrin receptor (TFRC) was significantly highly expressed in combination group than that in single agent groups, without affecting TPOR. Furthermore, the apoptosis of the combination group MDS cells could be partially reversed by ferric ammonium citrate (FAC), accompanied with decreased expression of TFRC. These results suggested that the combination of DFX and ELT synergistically induced apoptosis of MDS cells by enhancing iron deprivation-related pathway.

• Authors: Lei Huang, Mengyue Tian, Zhaoyun Liu, Chunyan Liu, Rong Fu
• Journal: Journal of investigative medicine : the official publication of the American Federation for Clinical Research (J Investig Med) Vol. 70 Issue 4 Pg. 953-962 (04 2022) ISSN: 1708-8267 [Electronic] England
• PMID: 34921125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Benzoates
• Hydrazines
• Iron Chelating Agents
• Pyrazoles
• Iron
• eltrombopag
• Deferasirox

Topics

• Apoptosis
• Benzoates
• Deferasirox (pharmacology, therapeutic use)
• Humans
• Hydrazines
• Iron (pharmacology)
• Iron Chelating Agents (pharmacology, therapeutic use)
• Myelodysplastic Syndromes (drug therapy, genetics)
• Pyrazoles
• Thrombocytopenia (complications, drug therapy)