Low-dose salinomycin induces anti-leukemic responses in AML and MLL

Area of Science:

• Oncology
• Pharmacology
• Cell Biology

Background:

• Drug repurposing is a cost-effective strategy for developing new anti-cancer therapies.
• Salinomycin, an ionophore, was previously identified for breast cancer but its potential in leukemia remains unexplored.

Purpose of the Study:

• To investigate the anti-leukemic efficacy of low-dose salinomycin.
• To assess the safety profile of salinomycin in normal hematopoietic cells.
• To elucidate the molecular mechanisms underlying salinomycin's anti-leukemic effects.

Main Methods:

• Treatment of acute myeloid leukemia (AML) and mixed lineage leukemia rearranged (MLLr) cell lines, primary cells, and patient samples with submicromolar concentrations of salinomycin.
• Colony formation assays using normal hematopoietic cells.
• In vivo transplantation studies using primary cells from leukemia patients.
• Bioinformatic analysis of a 17-gene signature in MLLr cells.
• Western blot analysis for p62/Sqstm1 protein expression.

Main Results:

• Submicromolar salinomycin demonstrated sensitivity in AML and MLLr cell lines, primary cells, and patient samples.
• Salinomycin did not affect the colony formation of normal hematopoietic cells, indicating a lack of hemotoxicity.
• Salinomycin treatment led to a loss of leukemia repopulation ability in transplanted primary cells, improving recipient survival.
• Bioinformatic analysis revealed immunomodulatory pathways and identified p62/Sqstm1 as a key gene, suggesting its role in salinomycin's mechanism via autophagy.

Conclusions:

• Low-dose salinomycin exhibits potent anti-leukemic activity at non-hemotoxic concentrations.
• Salinomycin's mechanism involves the induction of autophagic responses, potentially through p62/Sqstm1.
• Further clinical investigation of salinomycin, alone or in combination therapies, is warranted for leukemia treatment.