Tumor necrosis factor-related apoptosis-inducing ligand cooperates with anticancer drugs to overcome chemoresistance in antiapoptotic Bcl-2 family members expressing Jurkat cells
Tumor necrosis factor-related apoptosis-inducing ligand cooperates with anticancer drugs to overcome chemoresistance in antiapoptotic Bcl-2 family members expressing Jurkat cells
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DOI：
10.1158/1078-0432.ccr-1365-02
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发表时间：
2004-02-15
影响因子：
11.5
通讯作者：
Patrone, F
中科院分区：
文献类型：
--
作者：
Ballestrero, A;Nencioni, A;Patrone, F
目的：抗凋亡Bcl-2家族成员的过表达最近与几种人类恶性肿瘤，特别是淋巴瘤对化疗/放疗的抵抗有关。因此，在治疗方法中需要绕过这种耐药机制的创新方法。该研究评估了在Jurkat细胞模型中，通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）激活死亡受体途径是否可以克服与Bcl-2和Bcl-x（L）过表达相关的化学抗性。我们利用遗传修饰的Jurkat细胞来评估Bcl-2或Bcl-x（L）过表达对抗癌药物阿霉素产生的细胞毒性作用的影响，依托泊苷、奥沙利铂和TRAIL。通过切割半胱天冬酶-8和-3检测半胱天冬酶活化。用DiOC染色和流式细胞术评估线粒体跨膜电位。结果：Bcl-2和Bcl-x（L）过表达的Jurkat细胞对抗癌药物诱导的细胞溶解有保护作用，而caspase-8的缺失对细胞溶解无保护作用。然而，Bcl-2/Bcl-x（L）Jurkat细胞保留了对TRAIL诱导的细胞溶解的一些敏感性。在化学抗性细胞中检测到TRAIL与本研究中使用的任何抗胚细胞剂的组合的高度协同细胞毒性作用。结论：TRAIL联合常规抗癌药物治疗抗凋亡Bcl-2家族蛋白表达的恶性肿瘤可能是有效的。
Purpose: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-x(L) overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell modelExperimental Design: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-x(L) overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC, and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk.Results: Bcl-2 and Bcl-x(L) overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-x(L) Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activationConclusions: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.