Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 3, pp 583–591

Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells

  • Anna Fyrberg
  • Curt Peterson
  • Bertil Kågedal
  • Kourosh Lotfi
Original Article

DOI: 10.1007/s00280-010-1524-5

Cite this article as:
Fyrberg, A., Peterson, C., Kågedal, B. et al. Cancer Chemother Pharmacol (2011) 68: 583. doi:10.1007/s00280-010-1524-5

Abstract

Purpose

To characterize resistance mechanisms to the nucleoside analog 9-β-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant.

Methods

A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of AraG. Cytotoxicity of AraG and cross-resistance to other compounds were evaluated using a standard cytotoxicity assay.

Results

Gene expression microarray analysis revealed that fetal hemoglobin genes and the multidrug resistance ABCB1 gene, encoding the drug efflux pump P-gp, were the most highly upregulated genes in the resistant cells, while genes traditionally associated with nucleoside analog resistance were not. Fetal hemoglobin and ABCB1 induction can be due to global DNA hypomethylation. This phenomenon was studied using AraG during a period of 4 weeks in MOLT-4 cells and the lung adenocarcinoma cell line A549, leading to up-regulation of hemoglobin gamma and ABCB1 as well as DNA hypomethylation. Inhibiting P-gp in the AraG-resistant MOLT-4 cells led to decreased proliferation, reduced hemoglobin expression, and highly induced ABCB1 expression.

Conclusions

We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.

Keywords

9-β-D-arabinofuranosylguanine Fetal hemoglobin P-glycoprotein Microarray Hypomethylation 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Anna Fyrberg
    • 1
  • Curt Peterson
    • 1
  • Bertil Kågedal
    • 2
  • Kourosh Lotfi
    • 1
    • 3
  1. 1.Division of Drug Research/Clinical Pharmacology, Department of Medicine and Health, Faculty of Health SciencesLinköping UniversityLinköpingSweden
  2. 2.Division of Clinical Chemistry, Department of Clinical and Experimental Medicine, Faculty of Health SciencesLinköping UniversityLinköpingSweden
  3. 3.Department of HematologyLinköping University HospitalLinköpingSweden

Personalised recommendations