Solute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines

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dc.contributor.authorKutyna, M.M.
dc.contributor.authorLoone, S.
dc.contributor.authorSaunders, V.A.
dc.contributor.authorWhite, D.L.
dc.contributor.authorKok, C.H.
dc.contributor.authorHiwase, D.K.
dc.date.issued2023
dc.description.abstractAzacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance. AML cell lines were exposed to increasing concentrations of AZA to create resistant clones. 14C-AZA IUR was significantly lower in MOLM-13- (1.65 ± 0.08 ng vs. 5.79 ± 0.18 ng; p < 0.0001) and SKM-1- (1.10 ± 0.08 vs. 5.08 ± 0.26 ng; p < 0.0001) resistant cells compared to respective parental cells. Importantly, 14C-AZA IUR progressively reduced with downregulation of SLC29A1 expression in MOLM-13- and SKM-1-resistant cells. Furthermore, nitrobenzyl mercaptopurine riboside, an SLC29A inhibitor, reduced 14C-AZA IUR in MOLM-13 (5.79 ± 0.18 vs. 2.07 ± 0.23, p < 0.0001) and SKM-1-naive cells (5.08 ± 2.59 vs. 1.39 ± 0.19, p = 0.0002) and reduced efficacy of AZA. As the expression of cellular efflux pumps such as ABCB1 and ABCG2 did not change in AZA-resistant cells, they are unlikely contribute to AZA resistance. Therefore, the current study provides a causal link between in vitro AZA resistance and downregulation of cellular influx transporter SLC29A1.
dc.description.statementofresponsibilityMonika M. Kutyna, Sophie Loone, Verity A. Saunders, Deborah L. White, Chung H. Kok, and Devendra K. Hiwase
dc.identifier.citationInternational Journal of Molecular Sciences, 2023; 24(4):3553-1-3553-14
dc.identifier.doi10.3390/ijms24043553
dc.identifier.issn1661-6596
dc.identifier.issn1422-0067
dc.identifier.orcidKutyna, M.M. [0000-0003-2315-091X]
dc.identifier.orcidWhite, D.L. [0000-0003-4844-333X]
dc.identifier.orcidKok, C.H. [0000-0002-3181-7852]
dc.identifier.orcidHiwase, D.K. [0000-0002-6666-3056]
dc.identifier.urihttps://hdl.handle.net/2440/140172
dc.language.isoen
dc.publisherMDPI AG
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1195517
dc.rights© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
dc.source.urihttps://doi.org/10.3390/ijms24043553
dc.subjectazacitidine; SLC29A1; acquired/secondary resistance; leukemia; AML; MDS; cytotoxicity
dc.subject.meshCell Line, Tumor
dc.subject.meshHumans
dc.subject.meshAzacitidine
dc.subject.meshEquilibrative Nucleoside Transporter 1
dc.subject.meshDown-Regulation
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshLeukemia, Myeloid, Acute
dc.titleSolute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines
dc.typeJournal article
pubs.publication-statusPublished

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