Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.
Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.
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BH3模拟物与紫杉醇在慢性粒细胞白血病细胞中的协同作用机制：Mcl-1抑制。
DOI：
10.1016/j.ejps.2015.01.003
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
张志超
中科院分区：
文献类型：
--
作者：
宋婷;柴高波;张志超
当酪氨酸激酶抑制剂（TKI）出现原发性或继发性耐药时，紫杉醇是慢性粒细胞白血病（CML）的替代化疗药物，因为紫杉醇可以绕过CML中与p53和fas配体途径相关的凋亡缺陷。然而，高水平的Bcl-2家族蛋白在CML中可以抵抗紫杉醇诱导的凋亡。在此，我们利用两种BH 3模拟物ABT-737和S1来研究BH 3模拟物与紫杉醇联合治疗CML细胞的潜力，并阐明BH 3模拟物与紫杉醇协同作用的机制。S1单药可诱导K562细胞凋亡，而ABT-737则无明显作用。但两种药物均能通过内源性凋亡途径与紫杉醇协同作用。通过使用Bcl-2 siRNA、Bcl-XL siRNA和Mcl-1 siRNA，我们发现虽然三个成员中的每一个都表现出阻断紫杉醇诱导的凋亡的活性，但Mcl-1是紫杉醇与ABT-737或S1之间协同作用的决定因素。此外，紫杉醇/ABT 737协同作用以显著上调Bim以从Mcl-1置换巴克，而S1直接结合Mcl-1以释放Bim和巴克两者。因此，ABT-737和S1通过抑制Mcl-1、通过Bim拮抗Mcl-1间接抑制或通过与Mcl-1本身结合直接抑制而使CML对紫杉醇敏感。最后，JNK/Bim通路的激活被确定为ABT-737/紫杉醇协同作用的顶端机制。总之，我们的结果证明了BH 3模拟物和紫杉醇在杀死CML细胞中的有效协同作用，并揭示了Mcl-1在介导这些药物的协同作用中的重要作用。
Paclitaxel is an alternative chemotherapeutic agent for chronic myelogenous leukemia (CML) when primary or secondary resistance of tyrosine kinase inhibitors (TKI) is emerging, because paclitaxel could bypass the apoptotic deficiencies linked to p53 and fas ligand pathways in CML. However, high levels of Bcl-2 family proteins in CML could resist paclitaxel-induced apoptosis. Herein, we utilized two BH3 mimetics ABT-737 andS1to study the potential of BH3 mimetics in combination with paclitaxel in treatment of CML cells and illustrated the mechanism by which BH3 mimetics synergize with paclitaxel. As a single agent,S1could induce apoptosis in CML-derived cell line K562, whereas ABT-737 was largely ineffective. However, both of the two agents could efficiently synergize with paclitaxel through intrinsic apoptosis pathway. By using Bcl-2 siRNA, Bcl-XL siRNA or Mcl-1 siRNA, we found although each of the three members exhibited activities to block paclitaxel-induced apoptosis, Mcl-1 was the determinant for the synergistic effect between paclitaxel and ABT-737 orS1. Furthermore, paclitaxel/ABT737 synergized to drastically upregulate Bim to displace Bak from Mcl-1, whereasS1directly binds Mcl-1 to release both Bim and Bak. As such, ABT-737 andS1sensitized CML to paclitaxel by Mcl-1 inhibition, indirect inhibition through Bim antagonizing Mcl-1, or direct inhibition through binding to Mcl-1 itself. Finally, activation of JNK/Bim pathway was identified as the apical mechanism for ABT-737/paclitaxel synergism. Together, our results demonstrated potent synergy between BH3 mimetics and paclitaxel in the killing of CML cells and revealed an important role for Mcl-1 in mediating synergism by these agents.
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影响因子：
11.2
作者：
Song JH;Kandasamy K;Zemskova M;Lin YW;Kraft AS
通讯作者：
Kraft AS
影响因子：
6.4
作者：
Zhichao Zhang;T. Song;Tiantai Zhang;Jin Gao;Guiye Wu;L. An;G. Du
通讯作者：
Zhichao Zhang;T. Song;Tiantai Zhang;Jin Gao;Guiye Wu;L. An;G. Du
DOI：
10.1096/fj.03-0322
发表时间：
2003-11
期刊：
The FASEB Journal
影响因子：
--
作者：
A. Jacquel;M. Herrant;L. Legros;N. Belhacéne;F. Luciano;G. Pagès;P. Hofman;P. Auberger
通讯作者：
A. Jacquel;M. Herrant;L. Legros;N. Belhacéne;F. Luciano;G. Pagès;P. Hofman;P. Auberger
DOI：
10.1073/pnas.0438011100
发表时间：
2003-03-04
影响因子：
11.1
作者：
Lei, K;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
11.4
作者：
K. Seiter;E. Feldman;F. Traganos;Xun Li;H. Halicka;Zbigniew Darzynkiewicz;C. A. Lederman;M. Romero;Tauseef Ahmed
通讯作者：
K. Seiter;E. Feldman;F. Traganos;Xun Li;H. Halicka;Zbigniew Darzynkiewicz;C. A. Lederman;M. Romero;Tauseef Ahmed