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IMP–GMP specific cytosolic 5′-nucleotidase regulates nucleotide pool and prodrug metabolism

Cividini, Federico and Filoni, Daniela Nicole and Pesi, Rossana and Allegrini, Simone and Camici, Marcella and Tozzi, Maria Grazia (2015) IMP–GMP specific cytosolic 5′-nucleotidase regulates nucleotide pool and prodrug metabolism. Biochimica et Biophysica Acta. General Subjects, Vol. 1850 (7), p. 1354-1361. ISSN 0304-4165. Article.

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DOI: 10.1016/j.bbagen.2015.03.017

Abstract

Background: Type II cytosolic 5′-nucleotidase (cN-II) catalyzes the hydrolysis of purine and, to some extent, of pyrimidine monophosphates. Recently, a number of papers demonstrated the involvement of cN-II in the mechanisms of resistance to antitumor drugs such as cytarabine, gemcitabine and fludarabine. Furthermore, cN-II is involved in drug resistance in patients affected by hematological malignancies influencing the clinical outcome. Although the implication of cN-II expression and/or activity appears to be correlated with drug resistance and poor prognosis, the molecular mechanism by which cN-II mediates drug resistance is still unknown.
Methods: HEK 293 cells carrying an expression vector coding for cN-II linked to green fluorescent protein (GFP) and a control vector without cN-II were utilized. A highly sensitive capillary electrophoresis method was applied for nucleotide pool determination and cytotoxicity exerted by drugs was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay.
Results: Over-expression of cN-II causes a drop of nucleoside triphosphate concentration and a general disturbance of nucleotide pool. Over-expressing cells were resistant to fludarabine, gemcitabine and cytarabine independently of cN-II ability to hydrolyze their monophosphates.
Conclusions: An increase of cN-II expression is sufficient to cause both a general disturbance of nucleotide pool and an increase of half maximal inhibitory concentration (IC50) of the drugs. Since the monophosphates of cytarabine and gemcitabine are not substrates of cN-II, the protection observed cannot be directly ascribed to drug inactivation.
General significance: Our results indicate that cN-II exerts a relevant role in nucleotide and drug metabolism through not only enzyme activity but also a mechanism involving a protein–protein interaction, thus playing a general regulatory role in cell survival.
Sentence: Resistance to fludarabine, gemcitabine and cytarabine can be determined by an increase of cN-II both through dephosphorylation of active drugs and perturbation of nucleotide pool.

Item Type:Article
ID Code:10893
Status:Published
Refereed:Yes
Uncontrolled Keywords:Chemotherapy, resistance, cN-II, fludarabine, gemcitabine, cytarabine
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
Publisher:Elsevier
ISSN:0304-4165
Deposited On:25 May 2015 11:16

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