TRAILblazing Strategies for Cancer Treatment

Abstract

In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. Thus, several so-called TRAIL receptor agonists (TRAs) were developed. Unfortunately, clinical testing of these TRAs did not reveal any significant anticancer activity, presumably due to inherent or acquired TRAIL resistance of most primary tumour cells. Since the potential power of TRAIL-based therapies still lies in TRAIL’s explicit cancer cell-selectivity, a desirable approach going forward for TRAIL-based cancer therapy is the identification of substances that sensitise tumour cells for TRAIL-induced apoptosis while sparing normal cells. Numerous of such TRAIL-sensitising strategies have been identified within the last decades. However, many of these approaches have not been verified in animal models, and therefore potential toxicity of these approaches has not been taken into consideration. Here, we critically summarise and discuss the status quo of TRAIL signalling in cancer cells and strategies to force tumour cells into undergoing apoptosis triggered by TRAIL as a cancer therapeutic approach. Moreover, we provide an overview and outlook on innovative and promising future TRAIL-based therapeutic strategies.

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

“…DcR-1 and DcR-2 are able to inhibit the TRAIL pathway (29,37). Since DcR-2 and TRAIL-R2 are coexpressed in HNSCC tumors (60), the efficacy of TRAILmediated HNSCC therapy needs validation (34,35). As the resistance to TRAIL seems to exist in most tumor cells (33)(34)(35), the trials of newly developed anti-TRAIL-R2-drug conjugate reagents coupling with anti-miR-372 strategies could be elaborated as a potent therapeutic approach with the aim of ameliorating oncogenesis (34)(35)(36).…”

“…As TRAIL-R1 and TRAIL-R2 are apoptosis triggers that are active specifically in cancer cells rather than healthy cells (31,32), TRAIL-based therapies have become potential cancer targeting strategies. However, targeting TRAIL has disappointing outcomes because resistance to TRAIL therapy is common in cancers (33)(34)(35)(36). Specifically, a previous study Abbreviations: BrdU, 5-bromo-2 ′ -deoxyuridine; CDDP, cisplatin; ChIP, Chromatin immunoprecipitation; DMOG, dimethyloxaloylglycine; EMT, epithelial-mesenchymal transition; FPKM, fragments per Kb of transcript per million mapped reads; HNSCC, head and neck squamous cell carcinoma; LATS2, large tumor suppressor kinase 2; miRNA, microRNA; MMP, mitochondrial membrane potential; Mut, mutation; NCMT, non-cancerous matched tissue; OSCC, oral squamous cell carcinoma; qRT-PCR, quantitative reverse transcription polymerase chain reaction; TCGA, The Cancer Genome Atlas; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; TRAIL-R1, tumor necrosis factor related apoptosis-inducing ligand receptor 1; TRAIL-R2, tumor necrosis factor related apoptosis-inducing ligand receptor 2; WT, wild type; ZBTB7A, zinc finger and BTB domain containing 7A.…”

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

“…In addition, because TRAIL provides an external trigger for apoptosis, it has the potential to overcome resistance to internal triggers of apoptosis after radiation or chemotherapy. There have been many excellent reviews on TRAIL biology and the mechanism of action with implication for therapeutic applications in recent years [2][3][4][5][6][7][8]. Here, we focus on the structure-function of TRAIL and extend our discussion to other members of the TNFSF/TNFRSF to illustrate the mechanism of signaling by reviewing the most up-to-date and relevant information from the scientific literature.…”

Intracranial Delivery of Synthetic mRNA Using Common Transfection Reagent

“…Its protein product can speci cally kill cancer cells without harming normal cells [9][10][11][12][13]. Owing to its tumor cell-speci c killing effect, TRAIL has been widely used in preclinical and clinical studies [12,[14][15][16][17][18][19][20][21][22][23]]. In the current study, we used synthetic TRAIL-mRNA as an example to verify whether this method of intracranial injection can be applied for the treatment of GBM.…”