Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737.
Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737.
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DOI：
10.1158/0008-5472.can-08-1418
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Letai A
中科院分区：
文献类型：
--
作者：
Kutuk O;Letai A
紫杉醇是一种微管靶向的抗肿瘤药物，广泛用于人类癌症。即使当肿瘤最初有反应时，尽管继续进行紫杉烷治疗，疾病的进展在许多最常见的上皮性癌症的治疗中也是非常常见的，包括乳腺癌。然而，癌细胞中紫杉醇耐药的机制还不完全清楚。我们的假设是，由bcl2家族控制的固有(或线粒体)细胞死亡途径的变化是获得性紫杉醇耐药的关键。在这里，我们发现紫杉醇激活了线粒体的凋亡途径，该途径可以被bcl2的过度表达所阻断。用小分子bcl2拮抗剂ABT-737治疗，可以恢复bcl2过表达细胞对紫杉醇的敏感性。为了研究在缺乏强制bcl2表达的情况下改变固有的凋亡途径的重要性，我们产生了两个独立的乳腺癌细胞株，它们对紫杉醇诱导的细胞凋亡具有获得性抵抗。在这些细胞系中，对紫杉醇的获得性耐药是通过增加抗凋亡的bcl2蛋白或减少促凋亡的bcl2蛋白来调节的。在这两种情况下，ABT-737都可以参与线粒体凋亡途径，以恢复紫杉醇对获得性紫杉醇耐药细胞株的敏感性。综上所述，这些发现表明，由bcl2蛋白家族成员控制的内在凋亡途径的改变可能是导致紫杉醇耐药的关键。此外，我们的结果表明，小分子bcl2拮抗剂与紫杉醇联合使用可能对紫杉醇耐药肿瘤患者有利，紫杉醇耐药肿瘤是一个非常普遍的肿瘤学问题。
Paclitaxel is a microtubule-targeting antineoplastic drug widely used in human cancers. Even when tumors are initially responsive, progression of disease despite continued taxane therapy is all too common in the treatment of many of the most common epithelial cancers, including breast cancer. However, the mechanisms underlying paclitaxel resistance in cancer cells are not completely understood. Our hypothesis is that changes in the intrinsic (or mitochondrial) cell death pathway controlled by the BCL-2 family are key to the development of acquired paclitaxel resistance. Here we show that paclitaxel activates the mitochondrial apoptosis pathway, which can be blocked by BCL-2 overexpression. Treatment with ABT-737, a small molecule BCL-2 antagonist, restores sensitivity to paclitaxel in BCL-2 overexpressing cells. To investigate the importance of changes in the intrinsic apoptotic pathway in the absence of enforced BCL-2 expression, we generated two independent breast cancer cell lines with acquired resistance to apoptosis induced by paclitaxel. In these lines, acquired resistance to paclitaxel is mediated either by increased antiapoptotic BCL-2 proteins or decreased proapoptotic BCL-2 proteins. In both cases, ABT-737 can engage the mitochondrial apoptosis pathway to restore sensitivity to paclitaxel to cell lines with acquired paclitaxel resistance. In summary, these findings suggest that alterations in the intrinsic apoptotic pathway controlled by BCL-2 protein family members may be crucial to causing paclitaxel resistance. Furthermore, our results suggest that combining small molecule BCL-2 antagonists with paclitaxel may offer benefit to patients with paclitaxel-resistant tumors, an oncologic problem of great prevalence.