Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide

Lotfi, Kourosh; Månsson, Emma; Chandra, Joya; Wang, Yuying; Xu, Dawei; Knaust, Eva; Spasokoukotskaja, Tatjana; Liliemark, Eva; Eriksson, Staffan; Albertioni, Freidoun

doi:10.1046/j.1365-2141.2001.02751.x

Cited by 30 publications

(24 citation statements)

References 35 publications

(33 reference statements)

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“…A number of studies have dealt with the possible role of cN-II in drug resistance (25)(26)(27)(28)(29). Purified recombinant human cN-II hydrolyzes the 5Ј-monophosphates of different purine and pyrimidinebased nucleoside analogs but shows negligible activity with cytosine-containing analogs (30).…”

Section: The Three Motifs Motif I (Dxdx[t/v]l) Motif Ii ([T/s]) mentioning

confidence: 99%

Crystal Structure of Human Cytosolic 5′-Nucleotidase II

Wallden

Stenmark

Nyman

et al. 2007

Journal of Biological Chemistry

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Cytosolic 5-nucleotidase II catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5-monophosphates and regulates the IMP and GMP pools within the cell. It possesses phosphotransferase activity and thereby also catalyzes the reverse reaction. Both reactions are allosterically activated by adeninebased nucleotides and 2,3-bisphosphoglycerate. We have solved structures of cytosolic 5-nucleotidase II as native protein (2.2 Å ) and in complex with adenosine (1.5 Å ) and beryllium trifluoride (2.15 Å ). The tetrameric enzyme is structurally similar to enzymes of the haloacid dehalogenase (HAD) superfamily, including mitochondrial 5(3)-deoxyribonucleotidase and cytosolic 5-nucleotidase III but possesses additional regulatory regions that contain two allosteric effector sites. At effector site 1 located near a subunit interface we modeled diadenosine tetraphosphate with one adenosine moiety in each subunit. This efficiently glues the tetramer subunits together in pairs. The model shows why diadenosine tetraphosphate but not diadenosine triphosphate activates the enzyme and supports a role for cN-II during apoptosis when the level of diadenosine tetraphosphate increases. We have also modeled 2,3-bisphosphoglycerate in effector site 1 using one phosphate site from each subunit. By comparing the structure of cytosolic 5-nucleotidase II with that of mitochondrial 5(3)-deoxyribonucleotidase in complex with dGMP, we identified residues involved in substrate recognition.Cytosolic 5Ј-nucleotidase II (cN-II), 2 also called purine 5Ј-nucleotidase, IMP-GMP specific nucleotidase or high K m 5Ј-nucleotidase, is one of the seven known mammalian 5Ј-nucleotidases that catalyze the dephosphorylation of ribo-and deoxyribonucleoside monophosphates to nucleoside and inorganic phosphate (1, 2). The seven enzymes differ in substrate specificity, subcellular location, and tissue-specific expression. Intracellular 5Ј-nucleotidases regulate nucleotide levels by counteracting the action of nucleoside kinases and competing with other enzymes that use the nucleoside monophosphates. This complex network of interactions contributes to maintain nucleotide pools in tune with the metabolic needs of the cell (1, 2).The structures of two of the six human intracellular 5Ј-nucleotidases, i.e. mitochondrial 5Ј(3Ј)-deoxyribonucleotidase (mdN) (3) and cytosolic 5Ј-nucleotidase III (cN-III) (PDB entry 2CN1) are known. The latter is almost identical to the published structure of mouse cN-III (4). Both mdN and cN-III belong to the haloacid dehalogenase (HAD) superfamily, which is defined by an ␣/␤-Rossmann-like domain and a smaller 4-helix bundle domain, which, however, is not present in all HAD superfamily enzymes. The intracellular 5Ј-nucleotidases share three conserved motifs that have been found in HAD superfamily enzymes such as phosphoserine phosphatase (5) , are located in the ␣/␤-Rossmann-like domain and build up the catalytic phosphate-binding site in these enzymes. Motif I is directly involved in the reaction mechanism of 5Ј-nucleotidases (3),...

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Section: The Three Motifs Motif I (Dxdx[t/v]l) Motif Ii ([T/s]) mentioning

confidence: 99%

Crystal Structure of Human Cytosolic 5′-Nucleotidase II

Wallden

Stenmark

Nyman

et al. 2007

Journal of Biological Chemistry

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“…Deoxycytidine kinase (dCK) is the rate-limiting enzyme in the biotransformation of nucleoside analogues and the increase in dCK activity may improve the efficacy of gemcitabine (7). In contrast, high expression of the catabolic enzymes 5V -nucleotidase (5V-NT) and cytidine deaminase (CDA) is associated with cellular resistance to gemcitabine (8,9). In addition to being incorporated into DNA, gemcitabine exerts its cytotoxicity by inhibiting ribonucleotide reductase.…”

Section: Introductionmentioning

confidence: 99%

Transcription Analysis of Human Equilibrative Nucleoside Transporter-1 Predicts Survival in Pancreas Cancer Patients Treated with Gemcitabine

et al. 2006

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Gene expression analysis may help the management of cancer patients, allowing the selection of subjects responding to treatment. The aim of this study was the characterization of expression pattern of genes involved in gemcitabine activity in pancreas tumor specimens and its correlation with treatment outcome. The role of drug transport and metabolism on gemcitabine cytotoxicity was examined with specific inhibitors, whereas transcription analysis of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5V -nucleotidase (5V -NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) was done by quantitative reverse transcription-PCR in tumor tissue isolated by laser microdissection from surgical or biopsy samples of 102 patients. Association between clinical outcome and gene expression levels was estimated using Kaplan-Meier method and Cox's proportional hazards model. Transport and metabolism had a key role on gemcitabine sensitivity in vitro; moreover, hENT1, dCK, 5V -NT, CDA, RRM1, and RRM2 were detectable in most tumor specimens. hENT1 expression was significantly correlated with clinical outcome. Patients with high levels of hENT1 had a significantly longer overall survival [median, 25.7; 95% confidence interval (95% CI), 17.6-33.7 months in the higher expression tertile versus median, 8.5; 95% CI, 7.0-9.9 months in the lower expression tertile]. Similar results were obtained with disease-free survival and time to disease progression, and the multivariate analysis confirmed the prognostic significance of hENT1. This study suggests that the expression levels of hENT1 may allow the stratification of patients based on their likelihood of survival, thus offering a potential new tool for treatment optimization. (Cancer Res 2006; 66(7): 3928-35)

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“…Because the production of ara-CTP depends on the cellular activation of ara-C, cellular factors that can regulate ara-C activation play a role in ara-C resistance (11)(12)(13)(14)(15)(16). Ara-C catabolism results from rapid deamination by cytidine deaminase to the non-toxic metabolite ara-U (2), while cytosolic 5'-nucleotidase II (cN-II) dephosphorylates ara-CMP (7), Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses…”

Section: Introductionmentioning

confidence: 99%

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

Yamauchi

2011

Int J Oncol

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Abstract. Cytarabine (ara-C) is the key drug for treatment of acute myeloid leukemia. Since intracellular cytarabine triphosphate (ara-CTP) is an active metabolite of ara-C, factors that reduce the amount of ara-CTP are known to induce drug resistance. However, these factors do not fully explain the development of resistance to ara-C. The present study was conducted to search for new candidate ara-C resistance factors, including those that are unrelated to ara-CTP production.

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Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide

Cited by 30 publications

References 35 publications

Crystal Structure of Human Cytosolic 5′-Nucleotidase II

Crystal Structure of Human Cytosolic 5′-Nucleotidase II

Transcription Analysis of Human Equilibrative Nucleoside Transporter-1 Predicts Survival in Pancreas Cancer Patients Treated with Gemcitabine

Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses

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