Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma Ionga (Linn), and is commonly used as a coloring and flavoring agent in food products. The oriental and Ayurvedic medicine has traditionally used curcumin in the treatment of diseases associated with injury and inflammation. The medicinal value of curcumin has now been well recognized as it has profound anti-inflammatory and anti-tumor activities and is under pre clinical trials for the treatment of cancer and inflammation. Human T cell leukemia 1 (HTLV-1) is a retrovirus that cause adult T cell leukemia (ATL), an aggressive and frequently fatal malignancy in USA and other parts of the world. Although the exact sequence of events that occur during the early stages of infection are not known in detail, the tumor cells express constitutively active growth signaling pathways and show dysregulated growth and tumorigenesis. Agents that can prevent the growth and survival of HTLV-1 transformed T cells will prove to be useful for the treatment of human T cell leukemia. In this study we propose to investigate the effect and mechanism of action of curcumin on the regulation of growth and survival in HTLV-1 transformed T cell leukemia. Using the HTLV-1 transformed T cell leukemia lines, HUT-102, MT-2, SLB-1 and C5/MJ, we will examine the effect of curcumin on the expression of cyclin D1 and 2 activation of caspases and cleavage of BID/PARP proteins and their association with the induction of growth arrest and apoptosis in T cell leukemia. We will also examine the effect of curcumin on the constitutively active JAK3-STAT5 and IP3K-AKT signaling pathways and their links to the regulation of growth and apoptosis in T cell leukemia. It is likely that this study will provide new information on the effects and mechanism of action of curcumin on T cell leukemia and further in vivo studies will determine their use in the treatment of human T cell leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA106207-01
Application #
6676114
Study Section
Special Emphasis Panel (ZAT1-CP (05))
Program Officer
Arya, Suresh
Project Start
2003-09-30
Project End
2005-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$189,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Muthian, Gladson; Raikwar, Himanshu P; Rajasingh, Johnson et al. (2006) 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res 83:1299-309
Rajasingh, Johnson; Raikwar, Himanshu P; Muthian, Gladson et al. (2006) Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. Biochem Biophys Res Commun 340:359-68
Raikwar, Himanshu P; Muthian, Gladson; Rajasingh, Johnson et al. (2006) PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2. J Neuroimmunol 178:76-86
Muthian, Gladson; Pradeep, Chellappan G; Sargapradeep, Kuttappan et al. (2006) Setaria digitata secreted filarial lipids modulate IL-12 signaling through JAK-STAT pathway leading to the development of Th1 response. Exp Parasitol 114:193-203
Rajasingh, Johnson; Bright, John J (2006) 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells. Exp Cell Res 312:2538-46
Raikwar, Himanshu P; Muthian, Gladson; Rajasingh, Johnson et al. (2005) PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167:99-107
Muthian, Gladson; Bright, John J (2004) Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. J Clin Immunol 24:542-52