Epothilone-paclitaxel resistant leukemic cells CEWdEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways
Epothilone-paclitaxel resistant leukemic cells CEWdEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways
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DOI：
10.1016/j.bcp.2007.05.006
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发表时间：
2007-08-01
影响因子：
5.8
通讯作者：
Pourgholami, Mohammad H.
中科院分区：
文献类型：
--
作者：
Khalilzadeh, Azita;Wangoo, Kiran T.;Pourgholami, Mohammad H.
细胞凋亡信号通路的激活改变或缺陷可能导致耐药性。在这里，我们评估的作用，凋亡介质在引发抗增殖反应的紫杉醇（PTX）的T细胞急性淋巴细胞白血病（ALL）细胞系CEM和埃坡霉素紫杉醇耐药的亚系CEM/dEpoB300。此外，将对PTX的细胞反应与由细胞响应于用阿苯达唑（ABZ;微管解聚剂）处理而引起的那些反应进行比较。在细胞增殖研究中，CEM细胞对PTX和ABZ均敏感，而CEM/dEpoB300细胞对PTX高度耐药（IC50分别为2.86 nM和30.26 nM）。相反，抗性细胞显示出对ABZ的敏感性增加2倍（CEM中为0.32 μ M，而CEM/dEpoB300中为0.16 μ M）。响应于PTX或ABZ处理（24、48和72 h）的半胱天冬酶-3活性和细胞色素c释放的分析揭示，与亲本细胞相比，抗性细胞对PTX的响应减弱，对ABZ的响应增强。对于促凋亡蛋白Bax观察到类似的模式。抗凋亡蛋白Bcl-2的水平在CEM/dEpoB300细胞中高度升高，并且在这些细胞中，ABZ比PTX更有效地降低Bcl-2水平。类似地，ABZ处理导致Mcl-1蛋白的显著下调。这些结果第一次揭示了ALL细胞对PTX产生耐药性后凋亡介质的变化以及这些PTX耐药细胞对ABZ的敏感性显著增加。皇冠版权所有（c）2007由爱思唯尔公司出版。All rights reserved.
Altered or deficient activation of apoptosis signalling pathways may contribute to drug resistance. Here, we assess the role of apoptotic mediators in eliciting an anti-proliferative response to paclitaxel (PTX) in a T cell acute lymphoblastic leukemia (ALL) cell line CEM and its epothilone-paclitaxel resistant sub-line CEM/dEpoB300. Furthermore, the cellular response to PTX was compared to those elicited by cells in response to treatment with albendazole (ABZ; a microtubule depolymerizing agent). In cell proliferation studies, CEM cells were sensitive to both PTX and ABZ, while the CEM/dEpoB300 cells were highly resistant to PTX (IC50 2.86 nM versus 30.26 nM, respectively). In contrast, the resistant cells showed a 2-fold increase in sensitivity to ABZ (0.32 mu M in CEM compared to 0.16 mu M in CEM/dEpoB300). Analysis of caspase-3 activity and cytochrome c release in response to PTX or ABZ treatment (24, 48 and 72 h) revealed that, compared to the parent cells, the resistant cells have diminished response to PTX and enhanced response to ABZ. A similar pattern was observed for the pro-apoptotic protein Bax. Levels of the anti-apoptotic protein Bcl-2 was highly elevated in CEM/dEpoB300 cells and in these cells, ABZ was more effective in lowering the Bcl-2 levels than PTX. Similarly, ABZ treatment led to profound down regulation of the Mcl-1 protein. These results reveal for the first time, the changes in apoptotic mediators following development of resistance to PTX in an ALL cell and the significantly increased sensitivity of these PTX resistant cells to ABZ. Crown Copyright (c) 2007 Published by Elsevier Inc. All rights reserved.