Abstract
The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.
Highlights
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the group of chemotherapeutic ingredients, which affects various tumor cells without targeting the normal cells [1]
Other studies presented that DR5 up-regulating upon combination therapy with TRAIL and paxilline was responsible for sensitizing TRAIL-resistance glioma cell to TRAIL-induced apoptosis mediated by a CCAAT/enhancer-binding proteins (C/EBP) homologous protein (CHOP)/GADD153-arbitrated process (Figure 5) [82]
The exact mechanisms contributing to the escape from TRAILinduced apoptosis and progress of resistance to TRAIL in tumor cells has not yet been found completely, it seems that down-regulating pro-apoptotic proteins and DR4/5, concomitant with up-regulating anti-apoptotic proteins along with activating some signaling axis plays an influential role in this regard [225, 226]
Summary
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the group of chemotherapeutic ingredients, which affects various tumor cells without targeting the normal cells [1]. Deregulation of various signaling molecules and pathways, such as Janus kinase (JAK) and P53, results eventually in up-regulation of TRAIL-receptors expression, leading to tumor cells elimination [3,4,5]. TRAIL as a cytokine is frequently expressed by immune cells and plays a prominent role in Tcell homeostasis and NK or T-cell mediated elimination of malignant cells [9, 10]. This cytokine is considered a type II transmembrane protein containing an extracellular domain, which generates its biologically active soluble form upon cleavage. We will describe TRAIL signaling and its regulation, as well as known mechanisms that contributed to cancer cell resistance to TRAIL therapy, and more importantly, will investigate the current approaches that resistance, ranging from combination therapy (using TRAIL along with other antitumor agents) to TRAIL targeted delivery by nanoparticles (NPs) and stem cells (SCs)
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