Tumor cell resistance to cytotoxic immunotherapy results from multiple mechanisms as described above, namely, the development of resistance to apoptosis-inducing stimuli. The hyperactivation of survival pathways and overexpression of anti-apoptotic gene products regulate, in large part, immunoresistance . Hence, interference with these anti-apoptotic survival pathways by pharmacological inhibitors targeting gene products in these pathways should inhibit synthesis and transcription of anti-apoptotic gene products and, hence, could sensitize the cells to various apoptotic stimuli. Several studies have been performed with a large number of pharmacologic and proteasome inhibitors which resulted in the sensitization to death ligand-induced apoptosis. Representative findings will illustrate their applications as immunosensitizing agents. For instance, the NF-kB inhibitors Bay11-7085 and DHMEQ have been shown to sensitize tumor cells to Fas ligand-induced apoptosis through inhibition of the transcription repressor YY1, that is under the regulation of NF-kB . Likewise, inhibitors of the p38 MAPK pathways, such as PP2, SB203580, also resulted in the inhibition of NF-kB and YY1 and sensitized tumor cells to Fas ligand-induced apoptosis . Similar findings achieved for Fas ligand were also obtained for sensitizing tumor cells to TRAIL-induced apoptosis through upregulation of DR5 . In addition, proteasome inhibitors such as Bortezomib and NPI 0052 were also found to sensitize tumor cells to both Fas ligand and TRAIL-induced apoptosis [63-66]. A recent study has addressed the role of the tumor microenvironment in the regulation of tumor cells sensitivity to TRAIL. Resistance to TRAIL might have been due to hypoxia [known to induce the upregulation of the hypoxy-inducing factor- 1a(HIF- 1a)] and this inhibits TRAIL-induced apoptosis [67, 68].
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