Trail receptor-targeted therapy : strategies to enhance DR4- and DR5-induced apoptosis

Cancer is one of the leading causes of death in the world, the number of new cases and deaths continues to increase. The induction of apoptosis, also called programmed cell death, in cancer cells is an important goal of anti-cancer agents. Standard treatment with radio- and chemotherapy, however, cause unwanted side effects and often lead to resistance due to insufficient efficacy. Therefore, biological therapeutics are developed as alternative treatment strategies. Tumour Necrosis Factor-related apoptosis-inducing ligand (TRAIL) is an example of a promising biological agent as it selectively induces apoptosis in cancer cells but not in healthy cells. In addition, TRAIL is well tolerated by patients. Unfortunately, TRAIL-induced apoptosis is hampered in approximately 50% of tumour cells due to obstructions at different levels in the apoptotic pathway.In this thesis, the mechanisms behind TRAIL-resistance of different cancer types were examined. This information was used to design rational combination strategies of TRAIL with other agents. The effectiveness of TRAIL-induced apoptosis is improved due to clustering of the membrane-bound receptors to which TRAIL binds, and because of changes in the ratio of apoptotic proteins. Additionally, it was demonstrated that the kinases JNK and p38 regulate apoptosis-activation by TRAIL, and that this effect was mediated by the protein Mcl-1.In summary, the results show that TRAIL-induced apoptosis in tumour cells can be improved by simultaneously modulating different molecular mechanisms. Further research should determine whether these possible combination strategies have added value for application in the clinic