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Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1 期刊论文

编号：

e5b5e4ad-d4b8-4b57-b329-e7e8b80a4bf4
作者：

Luedtke, Daniel A.#^[1]Su, Yongwei#^[2]Liu, Shuang^[2,3];Edwards, Holly^[4,5];Wang, Yue(王玥)^[6]Lin, Hai(林海)^[7]Taub, Jeffrey W.^[3,5,8];Ge, Yubin*^[1,3,4,5]
语种：

English
期刊：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE ISSN：1582-4934 2018 年 22 卷 12 期 (6099 - 6111) ; DEC
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关键词：

ABT-199 acute myeloid leukaemia Bcl-2 KPT-330 XPO1
摘要：

The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1. The combination of KPT-330 and ABT-199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT-330 treatment decreased Mcl-1 protein after apoptosis initiation. However, binding of Bim to Mcl-1 induced by ABT-199 was abrogated by KPT-330 at the same time as apoptosis initiation. KPT-330 treatment increased binding of Bcl-2 to Bim but was overcome by ABT-199 treatment, demonstrating that KPT-330 and ABT-199 reciprocally overcome apoptosis resistance. Mcl-1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT-330 treatment, alone and in combination with ABT-199, modulates Mcl-1, which plays an important role in the antileukaemic activity of the combination.
推荐引用方式
GB/T 7714：

Luedtke Daniel A.,Su Yongwei,Liu Shuang, et al. Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1 [J].JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2018,22(12):6099-6111.
APA：

Luedtke Daniel A.,Su Yongwei,Liu Shuang,Edwards Holly,&Ge Yubin.(2018).Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1 .JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,22(12):6099-6111.
MLA：

Luedtke Daniel A., et al. "Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1" .JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 22,12(2018):6099-6111.
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