ArticleCancer chemotherapy and pharmacology2022
Drug resistance to nelarabine in leukemia cell lines might be caused by reduced expression of deoxycytidine kinase through epigenetic mechanisms.
Article in Cancer chemotherapy and pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.
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Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action.Leukemia · 2025Pooled it
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- Cellular pharmacology of fludarabine: molecular determinants of transport and metabolism.Frontiers in pharmacology · 2026Review
- The niosomal nelarabine as a promising nano combination for retinoblastoma treatment: anAnnals of medicine and surgery (2012) · 2025Article
- A Bibliometric Analysis of Drug Resistance in Pediatric Acute Lymphoblastic Leukemia.Advanced biomedical research · 2025Article
- Current treatment strategies targeting histone deacetylase inhibitors in acute lymphocytic leukemia: a systematic review.Frontiers in oncology · 2024Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeDrug resistance is a serious problem in leukemia therapy. A novel purine nucleoside analogue, nelarabine, is available for the treatment of children with T cell acute lymphoblastic leukemia. We investigated the mechanisms of drug resistance to nelarabine.
methodsNelarabine-resistant cells were selected by stepwise and continuous exposure to nelarabine using the limiting dilution method in human B and T cell lymphoblastic leukemia cell lines. Expression analysis was performed using real-time polymerase chain reaction, and epigenetic analysis was performed using methylation-specific polymerase chain reaction and chromatin immunoprecipitation.
resultsThe RNA expression level for deoxycytidine kinase (dCK) was decreased in nelarabine-resistant leukemia cells. There were no differences between the parental and nelarabine-resistant leukemia cells in the methylation status of the promoter region of the dCK gene. In the chromatin immune precipitation assay, decreased acetylation of histones H3 and H4 bound to the dCK promoter was seen in the nelarabine-resistant cells when compared to the parental cells. Furthermore, treatment with a novel histone deacetylase inhibitor, vorinostat, promoted the cytotoxic effect of nelarabine along with increased expression of the dCK gene, and it increased acetylation of both histones H3 and H4 bound to the dCK promoter in nelarabine-resistant leukemia cells. The combination index showed that the effect of nelarabine and vorinostat was synergistic.
conclusionThis study reports that nelarabine with vorinostat can promote cytotoxicity in nelarabine-resistant leukemia cells through epigenetic mechanisms.
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