Journal
ONCOTARGET
Volume 5, Issue 12, Pages 4337-4346Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2016
Keywords
Acute myeloid leukemia; leukemic stem cell; new drugs; XIAP; Embelin
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Funding
- Ramon y Cajal program/Ministry of Economy [RYC-2011-07998]
- Premi Fi de Residencia Emili Letang of Hospital Clinic
- Rio Hortega fellowship (ISCIII)
- Plan Nacional [SAF2012-34352]
- AECC de Barcelona
- Fondo de Investigaciones Sanitarias [PI040135, PI041357, RD06/0020/0004]
- Fundacio Internacional Josep Carreras
- Obra Social La Caixa
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Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials.
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