Mechanisms of Drug Sensitization to TRA-8, an Agonistic Death Receptor 5 Antibody, Involve Modulation of the Intrinsic Apoptotic Pathway in Human Breast Cancer Cells
Mechanisms of Drug Sensitization to TRA-8, an Agonistic Death Receptor 5 Antibody, Involve Modulation of the Intrinsic Apoptotic Pathway in Human Breast Cancer Cells
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DOI：
10.1158/1541-7786.mcr-10-0133
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发表时间：
2011-04-01
影响因子：
5.2
通讯作者：
Buchsbaum, Donald J.
中科院分区：
文献类型：
--
作者：
Amm, Hope M.;Zhou, Tong;Buchsbaum, Donald J.
TRA-8，一种针对死亡受体5的单克隆抗体，可诱导多种癌细胞凋亡；然而，敏感程度从高度敏感到耐药不等。我们之前已经证明，使用化疗药物可以逆转对 TRA-8 的耐药性，但这种致敏背后的机制尚未完全清楚。在这里，我们检查了 TRA-8 与阿霉素或硼替佐米在乳腺癌细胞中的组合。在 TRA-8 耐药的 BT-474 和 T47D 细胞中，两种化疗药物协同使细胞对 TRA-8 细胞毒性敏感，并通过半胱天冬酶和 PARP 的裂解增强细胞凋亡的激活、降低 Bid、增加促凋亡 Bcl-2 蛋白以及增加线粒体膜去极化。阿霉素或硼替佐米与 TRA-8 联合还可以减少处理细胞中的 Bcl-XL 和 X 连锁凋亡抑制剂 (XIAP)。此外，用药理学调节剂 AT-101、BH3I-20 和 AT-406 靶向这些蛋白质，产生对 TRA-8 的敏化。 TRA-8 与抗凋亡 Bcl-2 蛋白抑制剂 AT-101 或 BH3I-20 结合，对 ZR-75-1、BT-474 和 T47D 细胞产生协同细胞毒性。 IAP 靶向化合物 AT-406 在 BT-474 细胞中与 TRA-8 具有协同作用，在 T47D 细胞中也有较小程度的协同作用。内在凋亡途径的激活是与 TRA-8 耐药乳腺癌细胞系致敏相关的常见机制。总的来说，这些研究表明 Bcl-2 和 IAP 蛋白家族通过调节内在的细胞凋亡途径参与 TRA-8 和化疗耐药。用新的药物靶向这些蛋白质可以使 TRA-8 耐药的乳腺癌细胞变得敏感，这表明这种方法可能代表了治疗乳腺癌的一种有效的治疗策略。摩尔癌症研究中心； 9(4)； 403-17。 (C) 2011 年 AACR。
TRA-8, a monoclonal antibody to death receptor 5 induces apoptosis in various cancer cells; however, the degree of sensitivity varies from highly sensitive to resistant. We have previously shown that resistance to TRA-8 can be reversed by using chemotherapeutic agents, but the mechanism underlying this sensitization was not fully understood. Here, we examined the combination of TRA-8 with doxorubicin or bortezomib in breast cancer cells. In TRA-8-resistant BT-474 and T47D cells, both chemotherapy agents synergistically sensitized cells to TRA-8 cytotoxicity with enhanced activation of apoptosis shown by cleavage of caspases and PARP, reduced Bid, increased proapoptotic Bcl-2 proteins, and increased mitochondrial membrane depolarization. Doxorubicin or bortezomib combined with TRA-8 also reduced Bcl-XL and X-linked inhibitors of apoptosis (XIAP) in treated cells. Furthermore, targeting these proteins with pharmacologic modulators, AT-101, BH3I-20 and AT-406, produced sensitization to TRA-8. TRA-8 combined with AT-101 or BH3I-20, inhibitors of antiapoptotic Bcl-2 proteins, produced synergistic cytotoxicity against ZR-75-1, BT-474, and T47D cells. The IAP-targeting compound, AT-406, was synergistic with TRA-8 in BT-474 cells, and to a lesser extent T47D cells. Activation of the intrinsic apoptotic pathway was a common mechanism associated with sensitization of TRA-8-resistant breast cancer cell lines. Collectively, these studies show that the Bcl-2 and IAP families of proteins are involved in TRA-8 and chemotherapy resistance via their modulation of the intrinsic apoptotic pathway. Targeting these proteins with novel agents sensitized TRA-8-resistant breast cancer cells, suggesting this approach may represent a potent therapeutic strategy in the treatment of breast cancer. Mol Cancer Res; 9(4); 403-17. (C) 2011 AACR.