Chemopreventive agents induce suppression of nuclear factor-kappaB leading to chemosensitization

Nuclear factor-kappaB (NF-kappaB), a transcription factor, is present normally in the cytoplasm as an inactive heterotrimer consisting of p50, p65, and IkappaBalpha subunits. When activated, NF-kappaB translocates to the nucleus as a p50-p65 heterodimer. This factor regulates the expression of various genes that control apoptosis, viral replication, tumorigenesis, various autoimmune diseases, and inflammation. NF-kappaB has been linked to the development of carcinogenesis for several reasons. First, various carcinogens and tumor promoters have been shown to activate NF-kappaB. Second, activation of NF-kappaB has been shown to block apoptosis and promote proliferation. Third, the tumor microenvironment can induce NF-kappaB activation. Fourth, constitutive expression of NF-kappaB is frequently found in tumor cells. Fifth, NF-kappaB activation induces resistance to chemotherapeutic agents. Sixth, several genes involved in tumor initiation, promotion, and metastasis are regulated by NF-kappaB. Seventh, various chemopreventive agents have been found to down-regulate the NF-kappaB activation. All these observation suggest that NF-kappaB could mediate tumorigenesis and thus can be used as a target for chemoprevention and for the treatment of cancer. Agents that suppress NF-kappaB activation can suppress the expression of genes involved in carcinogenesis and tumorigenesis in vivo.