The products of root of Curcuma longa (C.L.), usually contain three major components, curcumin (CUR; ~77%), demethoxycurcumin (~17%) and bis-demethoxycurcumin (~3%), they are commonly used as botanical dietary supplements. The long term goal of this research project is to develop a safe and effective strategy to use C.L. in preventing diseases including prostate cancer (PCa) and colorectal cancer (CRC) in the US. PCa remains the most common malignancy in American men with an estimated 192,280 new cases and 27,360 deaths were expected in 2009, whereas CRC is the second most common cause of cancer death among men ages 40 to 79 years, and the third leading cause of cancer mortality in women with an estimated 53,439 new cases were diagnosed in 2010. Rationale for the studies proposed in this application is derived from our published as well as preliminary unpublished studies demonstrating that: (1) in PCa, CUR shows in vivo inhibition of prostate tumors in nude mice human PC-3 xenograft and TRAMP mice; (2) in CRC, CUR induces apoptosis in human HT-29 colon cancer cells and inhibits NFkB; an analog of CUR dibenzoylmethane, inhibits adenomas in APCmin mice, and CRC in AOM-DSS mice; (3) CUR regulate Nrf2-dependent genes in the intestine using Nrf2 KO mice; (4) As TRAMP mouse PCa progresses, there is a loss of the anti-oxidative stress transcription factor Nrf2 and Nrf2-target genes; (5) Feeding TRAMP mice with CUR resulted in re-expression of Nrf2 and Nrf2-target gene UGT1A1 in the TRAMP prostate tumor correlating with tumor suppression; (6) Nrf2 gene is epigenetically regulated in TRAMP tumor and TRAMP C1 cell line through promoter CpG hypermethylation; (7) CUR reverses the methylation status of genes from a panel of 96 gene promoters of which their hypermethylation has been reported in human PCa; (8) CUR reverses the expression of Neurog1 gene, an established cancer methylation marker gene, with increase in de-methylation of Neurog1 gene coupled with increase Neurog1 mRNA and protein. Despite these promising results, however, significant gaps exist in our understanding of the epigenetic mechanisms of CUR/C.L. in disease prevention including cancer prevention of human PCa and CRC. Based on the results of our preliminary studies we hypothesize that C.L./CUR treatment causes epigenetic modifications leading to prevention of PCa and CRC with three Specific Aims: (1) To determine the epigenetic alterations elicited by Curcuma Longa (C.L.) in prevention of prostate tumorigenesis in TRAMP mice; (2) To investigate the chemopreventive efficacy and epigenetic alterations of C.L. in AOM/DSS-induced CRC; and (3) To elucidate the in vitro epigenetic mechanisms of regulation of the genes obtained from in vivo Aims one and two by C.L. in TRAMP C1, LNCaP, and HT29 cell culture system.
Curcuma longa (C.L.) is commonly used as a botanical dietary supplement. Better understanding of the molecular mechanism of C.L. via epigenetic alterations would enhance the use of C.L. in diseases prevention including prostate and colorectal cancers that would greatly benefits thousands of Americans.
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