Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy
Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy
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DOI：
10.1007/s00262-005-0676-3
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发表时间：
2006-01-01
影响因子：
5.8
通讯作者：
Murphy, WJ
中科院分区：
文献类型：
--
作者：
Sayers, TJ;Murphy, WJ
细胞凋亡在胚胎发生、成体组织稳态和细胞对应激刺激的反应中具有重要作用。因此，增加的细胞凋亡参与各种缺血性、退行性和免疫性疾病的发病机制。相反，导致细胞凋亡减少或消除的遗传畸变可促进肿瘤发生，并成为癌细胞对各种遗传毒性抗癌剂的抗性的基础。因此，详细了解细胞凋亡途径的控制可以帮助合理设计有效的治疗方法，用于各种人类疾病，包括癌症。促进细胞凋亡的一种主要方式涉及通过肿瘤坏死因子（TNF）超家族成员的信号传导。在结合到其适当的受体上时，一些TNF家族成员可以促进半胱天冬酶活化和凋亡。TNF的早期研究表明，有限数量的肿瘤细胞系暴露于TNF后可被诱导发生凋亡。TNF家族的另一个成员Fas配体（FasL）也已知在多种肿瘤细胞中诱导凋亡。虽然TNF和FasL可以有效地诱导有限数量的肿瘤细胞凋亡，这些药物的管理与极端的毒性。这种毒性阻碍了TNF或FasL用于癌症治疗的进一步发展。然而，在过去的8年中，TNF家族的另一个成员，TNF相关的凋亡诱导配体（Apo 2L/TRAIL）已被表征，其诱导比TNF或FasL更广泛的癌细胞凋亡。令人惊讶的是，大多数正常的非转化细胞对Apo 2L/TRAIL的凋亡作用具有相当的抗性。这种对癌细胞的选择性毒性是目前对Apo 2L/TRAIL作为潜在的新型抗癌疗法的热情的基础。在本次研讨会报告中，我们提供了一个简短的概述Apo 2L/TRAIL，其受体及其信号通路。我们讨论Apo 2L/TRAIL单独或联合放疗或化疗的抗肿瘤作用的研究结果。此外，我们提出了最近的信息，从我们的小组有关的可能的治疗效益相结合的Apo 2L/TRAIL与蛋白酶体抑制剂硼替佐米。
Apoptosis has an essential role in embryogenesis, adult tissue homeostasis and cellular responses to stressful stimuli. Therefore, increased apoptosis is involved in the pathogenesis of various ischaemic, degenerative and immune disorders. Conversely, genetic aberration that results in a reduction or abolition of apoptosis can promote tumorigenesis and underlie the resistance of cancer cells to various genotoxic anticancer agents. Therefore, a detailed knowledge of the control of apoptotic pathways could aid in the rational design of effective therapeutics for a variety of human diseases including cancer. One major way to promote apoptosis involves signaling through members of the tumor necrosis factor (TNF) superfamily. On binding to their appropriate receptors, some TNF family members can promote caspase activation and apoptosis. Early studies on TNF indicated that a limited number of tumor cell lines could be induced to undergo apoptosis on exposure to TNF. Another member of the TNF family Fas ligand (FasL) is also known to induce apoptosis in a variety of tumor cells. Although TNF and FasL can efficiently induce apoptosis in a limited number of tumor cells, administration of either of these agents is associated with extreme toxicity. This toxicity has precluded further development of either TNF or FasL for cancer therapy. However, within the last 8 years another member of the TNF family, TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has been characterized, which induces apoptosis of a wider range of cancer cells than either TNF or FasL. Surprisingly, most normal non-transformed cells are quite resistant to the apoptotic effects of Apo2L/TRAIL. This selective toxicity for cancer cells is the basis for the current enthusiasm for Apo2L/TRAIL as a potential novel anticancer therapy. In this symposium report, we provide a brief overview of Apo2L/TRAIL, its receptors and their signaling pathways. We discuss findings on the antitumor effects of Apo2L/TRAIL alone or in combination with radiotherapy or chemotherapy. In addition, we present recent information from our groups concerning the possible therapeutic benefits of combining Apo2L/TRAIL with the proteasome inhibitor bortezomib.