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

Rizzo, Siân, Varache, Mathieu ORCID: https://orcid.org/0000-0001-7166-2253, Sayers, Edward J. ORCID: https://orcid.org/0000-0002-2621-1119, Jones, Arwyn T. ORCID: https://orcid.org/0000-0003-2781-8905, Tonks, Alex ORCID: https://orcid.org/0000-0002-6073-4976, Thomas, David W. ORCID: https://orcid.org/0000-0001-7319-5820 and Ferguson, Elaine L. ORCID: https://orcid.org/0000-0002-0125-0234 2024. Modification of the antibiotic, colistin, with dextrin causes enhanced cytotoxicity and triggers apoptosis in myeloid leukemia. International Journal of Nanomedicine 19 , pp. 5419-5437. 10.2147/IJN.S449185

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Abstract

Introduction 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 confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Pharmacy Dentistry
Publisher:	Dove Medical Press
ISSN:	1176-9114
Funders:	Wellcome Trust, MRC
Date of First Compliant Deposit:	16 April 2024
Date of Acceptance:	16 April 2024
Last Modified:	17 Jun 2024 12:21
URI:	https://orca.cardiff.ac.uk/id/eprint/167996

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