論文

査読有り
2017年9月

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

ONCOTARGET
  • Satoshi Imanishi
  • ,
  • Ryoko Takahashi
  • ,
  • Seiichiro Katagiri
  • ,
  • Chiaki Kobayashi
  • ,
  • Tomohiro Umezu
  • ,
  • Kazuma Ohyashiki
  • ,
  • Junko H. Ohyashiki

8
41
開始ページ
69906
終了ページ
69915
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.18632/oncotarget.19436
出版者・発行元
IMPACT JOURNALS LLC

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 mu M), 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 mu M 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.

リンク情報
DOI
https://doi.org/10.18632/oncotarget.19436
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29050250
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000411153300056&DestApp=WOS_CPL
ID情報
  • DOI : 10.18632/oncotarget.19436
  • ISSN : 1949-2553
  • PubMed ID : 29050250
  • Web of Science ID : WOS:000411153300056

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