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.
Highlights
Pharmacotherapy for cancer uses one or more chemotherapeutic drugs with either a curative aim or to prolong life and manage symptoms
mitochondrial outer membrane permeabilisation (MOMP) is enabled by caspase-8-mediated cleavage of the B-cell chronic lymphocytic leukaemia (CLL)/lymphoma 2 (Bcl-2) homology (BH)3-only protein (Bid) generating truncated Bid [73], which translocates to the mitochondria and eventually activates the mitochondrial cascade by generating an oligomerisation [74,75] of Bcl-2-associated
These results suggest that several pathways and regulators work together in a concerted manner to mediate TRAIL-induced apoptosis and autophagy
Summary
Pharmacotherapy for cancer uses one or more chemotherapeutic drugs with either a curative aim or to prolong life and manage symptoms. Cancers 2019, 11, 456 sparing healthy cells thereby reducing severe side effects is urgently needed in pharmacological cancer therapy This “silver bullet” against cancer seemed close at hand in 1995 when tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) was introduced [1,2] and later shown to selectively induce apoptosis in tumour cells in vivo [3,4]. After much testing, this selectivity holds to this day, its efficacy to induce significant levels of apoptosis in some resistant cancers will have to be helped through additional means
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