Bypass NF-kappaB-mediated survival pathways by TRAIL and Smac.

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Activation of NF-kappaB is frequently associated with human malignancies. The involvement of NF-kappaB is in part attributed to its ability to activate various genes promoting cell survival. This property contributes to tumor development, aggressive tumor growth, and resistance to chemotherapy and radiation in cancer treatment. Thus, developing strategies to overcome NF-kappaB-mediated cell survival is critical to improve cancer prevention and therapy. Various reports have shown that inhibition of NF-kappaB promotes apoptosis and suppress tumor growth. However, as NF-kappaB has many important cellular functions, targeting NF-kappaB directly may lead to severe side effects, which is undesirable for chemoprevention applications. In this report, we described a novel approach using TRAIL and a Smac analog to overcome and bypass NF-kappaB activation in cancer treatment. Since this treatment has no effect on NF-kappaB activation and TRAIL offers tumor selectivity, these results provide a novel strategy with potentially low toxicity to overcome NF-kappaB activation in cancer cells, which has potential therapeutic benefit and chemopreventive applications.