Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells.
Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells.
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DOI：
10.18632/oncotarget.19436
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Ohyashiki JH
中科院分区：
文献类型：
--
作者：
Imanishi S;Takahashi R;Katagiri S;Kobayashi C;Umezu T;Ohyashiki K;Ohyashiki JH
先前的研究表明，嘧啶补救的下调是对5-氮杂胞苷（AZA）耐药的基础，表明从头嘧啶合成在AZA耐药中起重要作用。由于从头嘧啶合成被免疫调节剂特立氟胺及其前体药物来氟米特抑制，我们研究了AZA和特立氟胺联合治疗对AZA耐药的影响，以开发一种新的策略来消除和预防AZA耐药。特立氟胺显著抑制AZA耐药的人白血病细胞系（R-U937和R-HL-60）的生长，与AZA敏感的对应物（U937和HL-60）相比。在非毒性浓度的特立氟胺（1 μM）存在下，AZA诱导AZA耐药细胞和AZA耐药患者的白血病细胞凋亡。在1 μM特立氟胺存在下，AZA在AZA耐药细胞中作为DNA甲基转移酶3A抑制剂。尽管AZA敏感细胞在用AZA连续处理42天后获得AZA抗性，但在AZA存在下，用AZA和特立氟胺的组合连续处理的AZA敏感细胞的生长被显著抑制，证明组合处理防止了AZA抗性。这些结果表明，AZA和特立氟胺联合治疗可能是克服AZA耐药的新策略。
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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DOI：
10.1200/jco.2011.35.8135
发表时间：
2011-08-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Prébet T;Gore SD;Esterni B;Gardin C;Itzykson R;Thepot S;Dreyfus F;Rauzy OB;Recher C;Adès L;Quesnel B;Beach CL;Fenaux P;Vey N
通讯作者：
Vey N
影响因子：
11.5
作者：
Bar-Or, Amit;Pachner, Andrew;Menguy-Vacheron, Francoise;Kaplan, Johanne;Wiendl, Heinz
通讯作者：
Wiendl, Heinz
DOI：
10.1073/pnas.0808480105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Jao, Cindy Y.;Salic, Adrian
通讯作者：
Salic, Adrian
影响因子：
2.7
作者：
Raynal, Noel J. -M.;Momparler, Louise F.;Momparler, Richard L.
通讯作者：
Momparler, Richard L.
影响因子：
45.3
作者：
Fenaux, Pierre;Mufti, Ghulam J.;Silverman, Lewis R.
通讯作者：
Silverman, Lewis R.