期刊
PHARMACOLOGICAL RESEARCH
卷 151, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2019.104556
关键词
FLT3; Nucleotide metabolism; Pediatric acute leukemia; Quizartinib; Cytarabine; cN-II
资金
- Fundacion Ramon Areces [CIVP18A3914]
- FEDER (European Union)
- ADR fellowship (University of Barcelona)
- FPI fellowship (Ministerio de Economia y Empresa)
- Becas Chile (Gobierno de Chile)
- Ministerio de Ciencia, Innovacion y Universidades [RTI2018-094655-B-100]
Treatment of pediatric acute leukemia might involve combined therapies targeting the FMS-like tyrosine kinase 3 (FLT3) receptor (i.e. quizartinib - AC220) and nucleotide metabolism (cytarabine - AraC). This study addressed the possibility of FLT3 modulating nucleoside salvage processes and, eventually, cytarabine action. Bone marrow samples from 108 pediatric leukemia patients (B-cell precursor acute lymphoblastic leukemia, BCP-ALL: 83; T-ALL: 9; acute myeloid leukemia, AML: 16) were used to determine the mRNA expression levels of FLT3, the cytarabine activating kinase dCK, and the nucleotidases cN-II and SAMHD1. FLT3 mRNA levels positively correlated with dCK, cN-II and SAMHD1 in the studied cohort. FLT3 inhibition using AC220 promoted the expression of cN-II in MV4-11 cells. Indeed, inhibition of cN-II with anthraquinone-2,6-disulfonic acid (AdiS) further potentiated the synergistic action of AC220 and cytarabine, at low concentrations of this nucleoside analog. FLT3 inhibition also down-regulated phosphorylated forms of SAMHD1 in MV4-11 and SEM cells. Thus, inhibition of FLT3 may also target the biochemical machinery associated with nucleoside salvage, which may modulate the ability of nucleoside-derived drugs. In summary, this contribution highlights the need to expand current knowledge on the mechanistic events linking tyrosine-kinase receptors, likely to be druggable in cancer treatment, and nucleotide metabolism, particularly considering tumor cells undergo profound metabolic re-programming.
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