Oncotarget

Research Papers:

Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells

Satoshi Imanishi _, Ryoko Takahashi, Seiichiro Katagiri, Chiaki Kobayashi, Tomohiro Umezu, Kazuma Ohyasiki and Junko H. Ohyashiki

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Oncotarget. 2017; 8:69906-69915. https://doi.org/10.18632/oncotarget.19436

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Abstract

Satoshi Imanishi1, Ryoko Takahashi1, Seiichiro Katagiri2, Chiaki Kobayashi1,2, Tomohiro Umezu1,2, Kazuma Ohyashiki2 and Junko H. Ohyashiki1

1Department of Molecular Oncology, Institute for Medical Science, Tokyo Medical University, Nishi-Shinjuku, Shinjuku, Tokyo, Japan

2Department of Hematology, Tokyo Medical University, Nishi-Shinjuku, Shinjuku, Tokyo, Japan

Correspondence to:

Satoshi Imanishi, email: [email protected]

Keywords: azacytidine, teriflunomide, pyrimidine metabolism, sensitization

Abbreviations: AZA, azacytidine; UCK, uridine cytidine kinase; DNMT, DNA methyltransferase; MDS, myelodysplastic syndromes; AML, acute myeloid leukemia

Received: November 09, 2016     Accepted: June 19, 2017     Published: July 22, 2017

ABSTRACT

Previous studies showed that downregulation of pyrimidine salvage underlies resistance against 5-azacytidine (AZA), indicating an important role for de novo pyrimidine synthesis in AZA resistance. Because de novo pyrimidine synthesis is inhibited by the immunomodulator teriflunomide and its pro-drug leflunomide, we examined the effect of combined treatment with AZA and teriflunomide on AZA resistance to develop a novel strategy to cancel and prevent AZA resistance. Teriflunomide markedly inhibited the growth of AZA-resistant human leukemia cell lines (R-U937 and R-HL-60) in comparison with their AZA-sensitive counterparts (U937 and HL-60). In the presence of a non-toxic concentration of teriflunomide (1 μM), AZA induced apoptosis in AZA-resistant cells and leukemia cells from AZA-resistant patients. AZA acted as a DNA methyltransferase 3A inhibitor in AZA-resistant cells in the presence of 1 μM teriflunomide. Although AZA-sensitive cells acquired AZA resistance after continuous treatment with AZA for 42 days, the growth of AZA-sensitive cells continuously treated with the combination of AZA and teriflunomide was significantly inhibited in the presence of AZA, demonstrating that the combined treatment prevented AZA resistance. These results suggest that combined treatment with AZA and teriflunomide can be a novel strategy to overcome AZA resistance.


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