Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Pharmacol Res. 2020 May;155:104716. doi: 10.1016/j.phrs.2020.104716. Epub 2020 Feb 18.
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces the apoptosis pathway in tumor cells leading to tumor cell death. Because TRAIL induction can kill tumor cells, cancer researchers have developed many agents to target TRAIL and some of these agents have entered clinical trials in oncology. Unfortunately, these trials have failed for many reasons, including drug resistance, off-target toxicities, short half-life, and specifically in gene therapy due to the limited uptake of TRAIL genes by cancer cells. To address these drawbacks, translational researchers have utilized drug delivery platforms. Although, these platforms can improve TRAIL-based therapies, they are unable to sufficiently translate the full potential of TRAIL-targeting to clinically viable products. Herein, we first summarize the complex biology of TRAIL signaling, including TRAILs cross-talk with other signaling pathways and immune cells. Next, we focus on known resistant mechanisms to TRAIL-based therapies. Then, we discuss how nano-formulation has the potential to enhance the therapeutic efficacy of TRAIL protein. Finally, we specify strategies with the potential to overcome the challenges that cannot be addressed via nanotechnology alone, including the alternative methods of TRAIL-expressing circulating cells, tumor-targeting bacteria, viruses, and exosomes.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性地诱导肿瘤细胞中的凋亡途径，导致肿瘤细胞死亡。由于 TRAIL 的诱导可以杀死肿瘤细胞，癌症研究人员已经开发了许多针对 TRAIL 的药物，其中一些已经进入肿瘤学的临床试验。不幸的是，由于多种原因，这些试验都失败了，包括耐药性、脱靶毒性、半衰期短，特别是在基因治疗中，由于 TRAIL 基因被癌细胞摄取的有限性。为了解决这些缺点，转化研究人员利用了药物输送平台。尽管这些平台可以改善基于 TRAIL 的治疗方法，但它们无法充分发挥 TRAIL 靶向治疗的全部潜力，使其转化为临床可行的产品。在此，我们首先总结了 TRAIL 信号转导的复杂生物学，包括 TRAIL 与其他信号通路和免疫细胞的串扰。接下来，我们重点讨论了已知的 TRAIL 治疗耐药机制。然后，我们讨论了纳米制剂如何有可能增强 TRAIL 蛋白的治疗效果。最后，我们指定了一些策略，这些策略有可能克服单靠纳米技术无法解决的挑战，包括 TRAIL 表达循环细胞、肿瘤靶向细菌、病毒和外泌体的替代方法。
