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.
Bharti
Alok C
AC
Cytokine Research Section, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Aggarwal
Bharat B
BB
D021581:Active Transport, Cell Nucleus; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division; D002470:Cell Survival; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021122:Protein Subunits
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D016328:NF-kappa B; D021122:Protein Subunits