Cover Image

IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion

The nucleoside analogue cytarabine (ara-C) is part of standard treatment against acute myeloid leukaemia (AML). The efficacy of this therapy is dependent upon accumulation of the active triphosphate metabolite ara-CTP, which mis-incorporates into genomic DNA, triggering cell death. The deoxyribonucl...

Full description

Saved in:
Bibliographic Details
Main Authors: Yagüe-Capilla, Miriam (Author) , Dirks, Christopher (Author) , Eiden, Caroline (Author) , Fesenmayer, Sonja K. (Author) , Hormann, Femke M. (Author) , Klootsema, Yolande (Author) , Lilienthal, Ingrid (Author) , Zhang, Si Min (Author) , Herold, Nikolas (Author) , Rudd, Sean G. (Author)
Format: Article (Journal)
Language:English
Published: 19 February 2026
In: Molecular oncology
Year: 2026, Pages: 1-19
ISSN:1878-0261
DOI:10.1002/1878-0261.70226
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/1878-0261.70226
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/1878-0261.70226
Get full text
Author Notes:Miriam Yagüe-Capilla, Christopher Dirks, Caroline Eiden, Sonja K. Fesenmayer, Femke M. Hormann, Yolande Klootsema, Ingrid Lilienthal, Si Min Zhang, Nikolas Herold and Sean G. Rudd
Description
Summary:The nucleoside analogue cytarabine (ara-C) is part of standard treatment against acute myeloid leukaemia (AML). The efficacy of this therapy is dependent upon accumulation of the active triphosphate metabolite ara-CTP, which mis-incorporates into genomic DNA, triggering cell death. The deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) SAMHD1 can hydrolyse ara-CTP and thereby convert the active metabolite back to its inactive prodrug form. This constitutes a barrier to treatment efficacy and thus strategies to target SAMHD1 are warranted. SAMHD1 activity is allosterically regulated by nucleotides, which are synthesised in cells via distinct pathways. We screened a collection of drugs targeting nucleotide biosynthetic enzymes and identified that inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH), responsible for catalysing the rate-limiting step in guanine nucleotide biosynthesis, sensitises AML cell lines to ara-C in a SAMHD1-dependent manner. We show that approved drugs inhibiting IMPDH—mycophenolic acid and ribavirin—imbalance deoxyribonucleoside triphosphate pools and increase ara-C efficacy in SAMHD1-proficient, but not deficient, leukaemic cells. Altogether, we provide insight into SAMHD1 regulation in leukaemic cells and show how this process can be exploited by approved drugs to improve ara-C therapy.
Item Description:Gesehen am 09.04.2026
Physical Description:Online Resource
ISSN:1878-0261
DOI:10.1002/1878-0261.70226

Similar Items