Abstract
The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics. The present data from azoxymethane-initiated, dextran sulfate sodium-promoted colitis associated cancer (CAC) model strongly indicate the potential of rTRAIL in cancer prevention rather than in cancer therapeutics. Early treatment of rTRAIL significantly reduced colitis and CAC by inhibiting the recruitment of macrophages into the damaged mucosa and activating the scavenger activity with efferocytosis and the production of several growth factors. In contrast, late administration of rTRAIL as for anti-cancer effect did not decrease the initiation and development of CAC at all. Significant cancer preventing mechanisms of rTRAIL were identified. In the CAC model, anti-inflammation, regeneration, and efferocytosis was induced by treatment of TRAIL for 6 days, significant inhibitory activity was evident at 4 weeks and anti-oxidative and anti-inflammatory induction were noted at 12 weeks. Most importantly, TRAIL promoted tissue regeneration by enhancing the resolution of pathological inflammation through the activation of the NLRP3 inflammasome pathway. The results indicate that TRAIL reduces the induction of colitis and the initiation of CAC by inhibiting pro-inflammatory signaling and promoting tissue repair to maintain intestinal homeostasis through activation of the NLRP3 inflammasome. Therefore, TRAIL can be used as a chemopreventive agent against CAC, rather than as a therapeutic drug endowing apoptosis.
Highlights
The induction of apoptosis in cancer cells has been the focus of many cancer therapeutic strategies involving apoptosis-inducing agents since avoiding apoptosis is one of the ley hallmarks of cancer
The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics
Since Recombinant TRAIL (rTRAIL) has been known as anti-cancer drug that selectively kills several kinds of cancer cells without damaging normal cells [6], we first compared the influence of rTRAIL in progression of azoxymethane (AOM)initiatedand dextran sulfate sodium (DSS)-promoted colon carcinogenesis
Summary
The induction of apoptosis in cancer cells has been the focus of many cancer therapeutic strategies involving apoptosis-inducing agents since avoiding apoptosis is one of the ley hallmarks of cancer. Many recombinant preparations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or death receptor targeting monoclonal antibodies have been developed [1]. TRAIL is a member of the TNF ligand family that consists of 281 and 291 amino acid in the human and murine forms [2, 3]. TRAIL can bind to five different receptors: DR4 (TRAIL-R1), DR5 (TRAIL-R2), DcR1 (TRAIL-R3), DcR2 (TRAIL-R4) and osteoprotegerin. As exemplified by titles of publication like “Are we on the right TRAIL?” [9], “Targeting TRAIL towards the clinic” [10], “Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy [11], further rational design of TRAIL-based therapy combined with other modality or advances in administration using nano- or cell–carriers is needed as cancer therapeutics [12]
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