Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling

Knowledge of the emerging pathways of cell death downstream of the p53 tumo r suppressor and the TRAIL death-inducing ligand is suggesting ways to impr ove therapeutic design in cancer. In contrast to its unique G1 cell cycle a rresting mechanism that is maintained by p21(WAF1), there are signals trans duced by p53 to multiple apoptotic effectors perhaps due to the importance of apoptosis in suppressing tumors. There is evidence for cytoplasmic as we ll as mitochondrial activation of caspases downstream of p53, although in s ome cell lineages the signal ultimately involves the mitochondria. The TRAI L signaling pathway appears promising for therapeutic development despite s haring some similarities with the toxic Fas and TNF pathways, in terms of e ffector molecules and downstream signals. One of the key findings is the ti ssue specificity of cell death responses, a feature that could be exploited in strategies to widen the therapeutic window of combination cancer therap ies. Efforts continue to develop p53-targeted cancer therapy, and novel clu es to enhance or block specific effectors may improve therapeutic design.