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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Cross-resistance between different classes of antineoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P <0.001) and β protein (P <0.026), formed substantially lower amounts of the topo II-DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P <0.001) for the high K m and 134% (P <0.331) for the low K m 5′-NT in resistant cells. The high K m 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′triphosphate [40% decreased (P <0.045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P <0.001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

Original languageEnglish
Pages (from-to)339-346
Number of pages8
JournalBritish Journal of Haematology
Volume113
Issue number2
DOIs
Publication statusPublished - 2001

Fingerprint

Cladribine
Etoposide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pharmacology
Cell Line
5'-Nucleotidase
Cytarabine
Type II DNA Topoisomerase
gemcitabine
Nucleosides
DNA Topoisomerases
Nucleotides
Deoxycytidine Kinase
Deoxyribonucleosides
Multidrug Resistance-Associated Proteins
Daunorubicin
P-Glycoprotein
Combination Drug Therapy
Antineoplastic Agents

Keywords

  • 5′-nucleotidase
  • CD95
  • Cladribine
  • Deoxycytidine kinase
  • Etoposide

ASJC Scopus subject areas

  • Hematology

Cite this

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, T.; Liliemark, Eva; Eriksson, Staffan; Albertioni, Freidoun.

In: British Journal of Haematology, Vol. 113, No. 2, 2001, p. 339-346.

Research output: Contribution to journalArticle

Lotfi, Kourosh ; Månsson, Emma ; Chandra, Joya ; Wang, Yuying ; Xu, Dawei ; Knaust, Eva ; Spasokoukotskaja, T. ; Liliemark, Eva ; Eriksson, Staffan ; Albertioni, Freidoun. / Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide. In: British Journal of Haematology. 2001 ; Vol. 113, No. 2. pp. 339-346.
@article{b7deb518e38b4d7994e82bf1c1cc6209,
title = "Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide",
abstract = "Cross-resistance between different classes of antineoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P <0.001) and β protein (P <0.026), formed substantially lower amounts of the topo II-DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206{\%} (P <0.001) for the high K m and 134{\%} (P <0.331) for the low K m 5′-NT in resistant cells. The high K m 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′triphosphate [40{\%} decreased (P <0.045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167{\%}, P <0.001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.",
keywords = "5′-nucleotidase, CD95, Cladribine, Deoxycytidine kinase, Etoposide",
author = "Kourosh Lotfi and Emma M{\aa}nsson and Joya Chandra and Yuying Wang and Dawei Xu and Eva Knaust and T. Spasokoukotskaja and Eva Liliemark and Staffan Eriksson and Freidoun Albertioni",
year = "2001",
doi = "10.1046/j.1365-2141.2001.02751.x",
language = "English",
volume = "113",
pages = "339--346",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide

AU - Lotfi, Kourosh

AU - Månsson, Emma

AU - Chandra, Joya

AU - Wang, Yuying

AU - Xu, Dawei

AU - Knaust, Eva

AU - Spasokoukotskaja, T.

AU - Liliemark, Eva

AU - Eriksson, Staffan

AU - Albertioni, Freidoun

PY - 2001

Y1 - 2001

N2 - Cross-resistance between different classes of antineoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P <0.001) and β protein (P <0.026), formed substantially lower amounts of the topo II-DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P <0.001) for the high K m and 134% (P <0.331) for the low K m 5′-NT in resistant cells. The high K m 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′triphosphate [40% decreased (P <0.045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P <0.001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

AB - Cross-resistance between different classes of antineoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P <0.001) and β protein (P <0.026), formed substantially lower amounts of the topo II-DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P <0.001) for the high K m and 134% (P <0.331) for the low K m 5′-NT in resistant cells. The high K m 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′triphosphate [40% decreased (P <0.045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P <0.001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

KW - 5′-nucleotidase

KW - CD95

KW - Cladribine

KW - Deoxycytidine kinase

KW - Etoposide

UR - http://www.scopus.com/inward/record.url?scp=0035004335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035004335&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2141.2001.02751.x

DO - 10.1046/j.1365-2141.2001.02751.x

M3 - Article

VL - 113

SP - 339

EP - 346

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 2

ER -