Abstract
Melanoma as a very aggressive type of cancer is still in urgent need of improved treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and arginine deiminase (ADI-PEG20) are two of many suggested drugs for treating melanoma. Both have shown anti-tumor activities without harming normal cells. However, resistance to both drugs has also been noted. Studies on the mechanism of action of and resistance to these drugs provide multiple targets that can be utilized to increase the efficacy and overcome the resistance. As a result, combination strategies have been proposed for these drug candidates with various other agents, and achieved enhanced or synergistic anti-tumor effect. The combination of TRAIL and ADI-PEG20 as one example can greatly enhance the cytotoxicity to melanoma cells including those resistant to the single component of this combination. It is found that combination treatment generally can alter the expression of the components of cell signaling in melanoma cells to favor cell death. In this paper, the signaling of TRAIL and ADI-PEG20-induced arginine deprivation including the main mechanism of resistance to these drugs and exemplary combination strategies is discussed. Finally, factors hampering the clinical application of both drugs, current and future development to overcome these hurdles are briefly discussed.
Highlights
DcR1 lacks the death domain which is required for transducing the death signal, while DcR2 has only a truncated death domain, and OPG is a soluble protein with lower affinity for Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [8]
In our former investigation, we found that arginine deprivation can efficiently enhance TRAIL toxicity in melanoma cell lines which do not express argininosuccinate synthetase (ASS1)
This study found that in vitro, the supply of citrulline in the presence of rhArg1-PEG could reverse the antiproliferation effect of arginine deprivation on activated T cells, but in vivo, the increase of citrulline associated with arginine degradation by rhArg1-PEG could not prevent the adverse effect on T cells
Summary
Investigations on the resistance to TRAIL with melanoma and other cancer cells have been providing valuable information to design combination therapeutic strategies for TRAIL-resistant cancers. B-RAF inhibition was found to sensitize the resistant melanoma cells to TRAIL in an earlier study [50]. This discrepancy may be due to the fact that different B-RAF inhibitors were used. In our former investigation, we found that arginine deprivation can efficiently enhance TRAIL toxicity in melanoma cell lines which do not express argininosuccinate synthetase (ASS1). Normal cells have low demand on arginine and are able to synthesize arginine if needed This difference between cancer and normal cells makes ADT, such as TRAIL, a targeted therapy against cancer cells. The discussion is mainly on ADI-PEG20 based ADT (see diagram)
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