Gampa Siri Chandana, Garimella Sireesha V, Pandrangi SanthiLatha
Department of Biotechnology, Institute of Science, GITAM (Deemed to be University), Andhra Pradesh 530045, India.
Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be University), Andhra Pradesh 530045, India.
Cancer Drug Resist. 2023 Feb 1;6(1):78-102. doi: 10.20517/cdr.2022.82. eCollection 2023.
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells ; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL's potential as an anticancer agent.
肿瘤坏死因子相关凋亡诱导配体，也称为载脂蛋白2配体（TRAIL/Apo-2L），是一种细胞因子，通过与TRAIL-R1（DR4）和TRAIL-R2（DR5）死亡受体结合触发细胞凋亡。细胞凋亡通过外源性或内源性途径发生。重组人TRAIL（rhTRAIL）或TRAIL受体（TRAIL-R）激动剂的给药在癌细胞中比在正常细胞中更优先地促进细胞凋亡；这种现象在临床研究中也已观察到。rhTRAIL在临床试验中的疗效有限可能归因于耐药性、半衰期短、靶向递送问题和脱靶毒性。纳米颗粒是优异的药物和基因递送系统，其特征在于改善的通透性和滞留性、增加的稳定性和生物相容性以及精确靶向性。在本综述中，我们讨论了对TRAIL的耐药机制以及通过使用为将TRAIL肽、TRAIL-R激动剂和TRAIL基因递送至癌细胞而开发的基于纳米颗粒的制剂来克服TRAIL耐药性的方法。我们还讨论了化疗药物与TRAIL的联合应用方法。这些研究证明了TRAIL作为抗癌剂的潜力。
