Hypothesis-driven drug repurposing identifies new potential low-toxicity treatment strategies for acute myeloid leukemia patients
Year: 2026
Type: conference-paper
Abstract: Acute myeloid leukemia (AML) is a malignancy of hematopoietic progenitors that primarily affect older adults and is associated with poor outcomes. Although treatment with venetoclax and azacitidine has improved initial responses, most patients eventually develop resistance and relapse, underscoring the need for additional low toxicity therapeutic strategies. Several non oncology drugs are known to cause cytopenias in their primary indications, therefore we hypothesized that some compounds may also affect AML progenitors and could be repurposed as antileukemic treatments in novel combinations. To examine this, we tested single drugs and drug combinations ex vivo in AML patient samples and healthy bone marrow controls using short term screens and long-term culture assays. Leukemic subpopulations were monitored by multiparameter flow cytometry, and mechanistic analyses included transcriptomic profiling, metabolic assays, and immunofluorescent staining. From a panel of 20 low-toxicity, non oncologic compounds, we identified chloramphenicol (CHL), an antibiotic, and phenylbutazone, a non-steroidal anti-inflammatory drug, with antileukemic activity. Their effects were enhanced when combined or CHL combined with valproic acid (VPA), an antiepileptic. Both short and long term assays showed reduced AML viability and impaired expansion of immature leukemic populations, along with reduced clonogenic potential. Comparative testing suggested preferential activity against AML samples over healthy bone marrow progenitors, indicating a therapeutic window. Mechanistic studies revealed that CHL could suppress oxidative phosphorylation, while VPA inhibits protein translation programs; thus, the combination reduces ATP production and proliferation, and thereby induces cell cycle arrest and leukemic cell death. Overall, our findings highlight chloramphenicol-based combinations as promising AML repurposing candidates identified through a hypothesis driven selection strategy.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7154952685