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Siân Rizzo,1 Mathieu Varache,1 Edward J Sayers,2 Arwyn T Jones,2 Alex Tonks,3 David W Thomas,1 Elaine L Ferguson1 1Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK; 2School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK; 3Department of Haematology, School of Medicine, Cardiff University, Cardiff, UKCorrespondence: Elaine L Ferguson, Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK, Tel +44 2922 510663, Email FergusonEL@cardiff.ac.ukIntroduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different ‘subtypes’ in combination with current chemotherapies. We have previously developed dextrin–colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin’s anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin–colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin’s cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic.Results: Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell ... |