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bioRxiv · 10.1101/2023.11.09.565276

Modification of the antibiotic, colistin, with dextrin causes enhanced cytotoxicity and triggers apoptosis in myeloid leukemia

Rizzo, S.·Varache, M.·Sayers, E. J.·Jones, A. T.·Tonks, A.·Thomas, D. W.·Ferguson, E. L.
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Abstract

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 colistins 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 colistins cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic. Our results identified a conjugate (containing 8,000 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 confocal microscopy of fluorescently-labelled compounds showed both free and dextrin-conjugated colistin were endocytosed and co-localized in lysosomes and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization. Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote AMR and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/565276v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1cb7aaorg.highwire.dtl.DTLVardef@15e3574org.highwire.dtl.DTLVardef@7577aorg.highwire.dtl.DTLVardef@eb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Rizzo, S., Varache, M., Sayers, E. J., Jones, A. T., Tonks, A., Thomas, D. W., Ferguson, E. L.. 2023-11-13. Modification of the antibiotic, colistin, with dextrin causes enhanced cytotoxicity and triggers apoptosis in myeloid leukemia. https://doi.org/10.1101/2023.11.09.565276

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