Visit our Expo - Redox and Inflammation signaling 2012

Targeting Inflammatory Transcription Factor by Dietary Agents for
Prevention and Treatment of Cancer
Bharat B. Aggarwal, Ph.D.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, U.S.A.
NF-kB, a transcription factor, is present normally in the cytoplasm as an inactive
heterotrimer consisting of p50, p65 and IkBa subunits. When activated, NF-kB translocates
to the 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-kB has been linked to the development of carcinogenesis for several
reasons. First, various carcinogens and tumor promoters have been shown to activate NF-kB.
Second, activation of NF-kB has been shown to block apoptosis and promote proliferation.
Third, the tumor microenvironment can induce NF-kB activation. Fourth, constitutive
expression of NF-kB is frequently found in tumor cells. Fifth, NF-kB activation induces
resistance to chemotherapeutic agents. Fifth, several genes involved in tumor initiation,
promotion, and metastasis are regulated by NF-kB. Sixth, various chemopreventive agents
have been found to downregulate the NF-kB activation. All these observation suggest that
NF-kB could mediate tumorigenesis and thus can be used as a target for chemoprevention and
for the treatment of cancer. Besides NF-kB, we have also targeted AP-1 and STAT3, other
transcription factors that mediate tumorigenesis. We will present the data which shows that
phytochemicals derived from fruits, vegetables and spices are important inhibitors of NF-kB
activation, and can suppress the expression of genes involved in carcinogenesis and
tumorigenesis in vivo.
Recent references:
1 Shishodia, S., and Aggarwal B.B. Diosgenin Inhibits Osteoclastogenesis, Invasion,
and Proliferation Through the Downregulation of Akt, IkB Kinase Activation and NF-kB-
Regulated Gene Expression, Oncogene (in press)
2 Aggarwal BB, Shishodia S., Takada Y., Banerjee S., Newman RA, Bueso-Ramos CE,
and Price JE Curcumin Suppresses the Paclitaxel-induced NF-!B Pathway in Breast Cancer
Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice, Clinical Cancer
Research (in press).
3 Aggarwal BB, Ichikawa H. Molecular Targets and Anticancer Potential of Indole-3-
Carbinol and Its Derivatives. Cell Cycle. 2005 Sep 6;4(9) 1201-1215
4 Takada Y, Kobayashi Y, and Aggarwal BB. Evodiamine abolishes constitutive and
inducible NF-kappa B activation by inhibiting Ikappa Balpha kinase activation, thereby
suppressing NF-kappa B-regulated antiapoptotic and metastatic gene expression, upregulating
apoptosis, and inhibiting invasion.J. Biol Chem. 2005 Feb 14; 2005;280(17):17203-12
5 Takada Y, Andreeff M, Aggarwal BB. Indole-3-carbinol suppresses NF-{kappa}B
and I{kappa}B{alpha} kinase activation causing inhibition of expression of NF-{kappa}Bregulated
antiapoptotic and metastatic gene products and enhancement of apoptosis in
myeloid and leukemia cells. Blood. 2005 Apr 5; 2005 Jul 15;106(2):641-9.
6 Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Related Articles, Links Abstract
Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated
with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of
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