Abstract
Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.
Highlights
Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy
Due to the important role of intrinsic apoptosis pathways in melanoma cells, Bcl-2 proteins appear as critical targets for melanoma therapy [15,47], and efficient apoptosis induction was found for Bim and Puma [38,48,49]
TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy, which may apply for the treatment of cutaneous melanoma
Summary
A number of cellular mechanisms contribute to the development of cancer, which have been listed in the often-cited hallmarks of cancer [9]. Concerning therapy resistance, apoptosis deficiency may have the most decisive contribution. This is suggested by the principal need to eliminate the tumor cells, and apoptosis induction appears as the most common and most efficient way of doing so. BRAF inhibition in melanoma cells has been related to an induction of apoptosis as well as to a sensitization for other proapoptotic effectors. The stimulation of an anti-tumor immune response results in activation of cytotoxic T-lymphocytes, which express death ligands to trigger extrinsic proapoptotic pathways in target cancer cells [14]. Sensitization of melanoma cells for TRAIL-induced apoptosis may support an anti-tumor immune response, based on the expression of death ligands. In the light of the breakthrough of approved immune-stimulating therapies in melanoma, this issue gets a particular meaning [6,7]
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