Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines

Biochemical and Biophysical Research Communications
Alan Kambiz FotoohiFreidoun Albertioni

Abstract

Mechanisms of resistance to thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were investigated in human leukemia cell lines. We developed two 6-MP- and 6-TG-resistant cell lines from the human T-lymphoblastic cell line (MOLT-4) by prolonged exposure to these drugs. The resistant cells were highly cross resistant to 6-MP and 6-TG, and exhibited marked reduction in cellular uptake of 6-MP (70% and 80%, respectively). No significant modification of the activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase was observed. Real-time PCR of concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2) of resistant cells showed substantial reductions in expression of messenger RNAs. Small interfering RNA designed to silence the CNT3 and ENT2 genes down-regulated the expression of these genes in leukemia cells. These decreases were accompanied by reduction of transport of 6-MP (47% and 21%, respectively) as well as its cytocidal effect (30% and 21%, respectively). Taken together these results show that CNT3 and ENT2 play a key role in the transport of 6-MP and 6-TG by leukemia cells. From a clinical point of view de...Continue Reading

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Citations

Oct 12, 2013·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Hazhar KarimAlan Fotoohi
Dec 3, 2011·Nucleosides, Nucleotides & Nucleic Acids·Paula X Fernández-CalottiMarçal Pastor-Anglada
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Jul 5, 2011·Biochemical and Biophysical Research Communications·Hazhar KarimFreidoun Albertioni
Dec 18, 2013·Biochemical and Biophysical Research Communications·Masahiro KanekoShin-Ichiro Takahashi
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