Therapeutic applications of TRAIL receptor agonists in cancer and beyond.
Therapeutic applications of TRAIL receptor agonists in cancer and beyond.
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DOI：
10.1016/j.pharmthera.2015.09.001
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发表时间：
2015-11
影响因子：
13.5
通讯作者：
Griffith TS
中科院分区：
文献类型：
--
作者：
Amarante-Mendes GP;Griffith TS
TRAIL/Apo-2L是TNF超家族的成员，在1995年首次被描述为一种凋亡诱导细胞因子。与TNF和Fas配体类似，TRAIL死亡受体三聚化后以半胱天冬酶依赖的方式诱导细胞凋亡。由于肿瘤细胞显示出对该细胞因子特别敏感，而正常细胞/组织被证明是抗性的，沿着能够合成和释放TRAIL，因此很快认识到TRAIL可能用作我们对抗癌症的主要生理武器之一。与此一致，许多研究实验室和制药公司已经尝试通过开发重组形式的TRAIL或TRAIL受体激动剂（例如，受体特异性mAb）用于治疗目的。在这篇综述文章中，我们将描述TRAIL用于诱导不同细胞死亡程序的生化途径。我们还将总结与此途径相关的临床试验，并讨论TRAIL相关疗法的可能新用途。近年来，TRAIL的生理学重要性已经从作为一种杀肿瘤分子扩展到对许多临床环境至关重要的分子-从感染性疾病和自身免疫到心血管异常。我们还将强调一些这些条件下的TRAIL/TRAIL受体系统的调制可能在未来的目标。
TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings — ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future.