Prostate cancer is the second leading cause of cancer deaths in the U.S., exceeded only by lung cancer. Epidemiological studies suggest that diet plays a crucial role in preventing prostate cancer. High intake of dark green leafy vegetables, fruits and soy products, which are rich in polyphenolic compounds, has been linked to low rate of prostate cancer in Asian men. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and tumor growth inhibitory activity. Our preliminary data indicate that combined curcumin/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) treatment induces apoptosis in prostate cancer cell lines characterized by binding of annexin V, activation of procaspases-3, -8, and -9, and the release of cytochrome c from mitochondria. In addition, prostate cancer cells express high levels of constitutively active NF-KappaB, which is inhibited by curcumin. Moreover, inhibition of NF-KappaB by siRNA or DN-lkappaBalpha (NF-KappaB inhibitor) sensitizes prostate tumor cells to TRAIL without curcumin. These results lead us to hypothesize that NF-kappaB mediates resistance of prostate cancer cells to TRAIL, and curcumin sensitizes them to TRAIL-induced apoptosis by inhibiting NF-KappaB and the expression of NF-kappaB dependent antiapoptotic gene products. The proposed studies have three goals: a) to determine the mechanism by which curcumin inhibits NF-KappaB activation, b) to determine whether curcumin sensitizes tumor cells to TRAIL by inhibiting NF-KappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and inhibitors of apoptosis protein family members (lAPs), and c) to explore therapeutic efficacy of combined curcumin/TRAIL regimen against hormone-refractory prostate tumor xenografts. Understanding the mechanism by which curcumin inhibits NF-KappaB activation and sensitizes prostate cancer cells to TRAIL could pave the way for developing this novel treatment strategy as an adjunct to the conventional treatments for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA102516-01A2
Application #
6917402
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Arya, Suresh
Project Start
2005-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$154,800
Indirect Cost
Name
Henry Ford Health System
Department
Surgery
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202