It is becoming apparent that the major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. Traditionally, nutritional compounds in """"""""folk medicine"""""""" are used in an unmodified form, as concentrated extracts. Given the fact that the human diet consists of multiple nutrients, it is likely that nutrients in the diet act synergistically to provide health benefits. The concept that food components act in synergism is not new. Centuries ago Hippocrates, the father of medicine, stated """"""""Let food be thy medicine, and let thy medicine be food."""""""" Based on this rationale we propose to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA) and curcumin (CCM). Our recent studies demonstrate that DHA induced apoptosis in breast cancer cells via enhanced expression of a key cell cycle regulator, p21. Data from other laboratories indicate that CCM also induces p21 expression. Expression of p21 is regulated upstream through multiple mechanisms, including ceramide, peroxisome proliferator-activated receptor-gamma (PPAR?), and p53-mediated pathways. It is apparent that these mediators can be regulated by DHA and/or CCM through common and divergent pathways that may cause a synergistic effect on p21 expression. Our central hypothesis is that DHA and CCM initiate common and divergent cellular pathways that synergistically induce apoptosis by regulating p21 expression. We will test our hypothesis using two specific aims:
Specific Aim 1 : Determine the synergistic effect of DHA and CCM on breast cancer cells. We will test combinations of DHA and CCM to characterize their apoptotic effects in different breast cancer cell lines. We will investigate common (ceramide formation) and divergent (PPAR? and p53 activation/expression) pathways for their synergistic effects on p21 expression.
Specific Aim 2 : Determine the preventive/therapeutic effects of DHA and CCM in a breast cancer model. We anticipate that combined treatment with DHA and CCM will be more effective than treatment with DHA or CCM alone in preventing breast cancer development. We will use breast cancer xenograft and carcinogen-induced breast cancer models to further confirm the common (ceramide) and divergent (PPAR? and/or p53) signaling pathways on the synergistic induction of p21 expression by DHA and CCM. The proposed investigation is innovative because the synergy of DHA and CCM has never been studied in any cancer model. Our studies are significant because the study outcome will lead to further investigation to determine whether combinations of nutrients provide synergistic effects to prevent breast cancer to those at a high risk of developing cancer as well as to prevent the recurrence or spread to other tissues after initial chemotherapy. We anticipate that the results of this study will help us develop an expanded research project for a future R01 grant application. Based on these studies, we will propose studies on different cancer models for the prevention, treatment, and reoccurrence of tumors using combinations of other nutritional compounds.

Public Health Relevance

The proposed study is based on the rationale that the human diet consists of multiple nutrients;it is likely that nutrients in the diet act synergistically to provide health benefits. We propose to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric. The relevance of the proposed project to public health is that it will provide helpful information for combining dietary components to prevent cancer initiation and progression, especially for those at high risk. The outcome of this study will also help future cancer patients to prevent the recurrence or spread of cancer by clarifying the right combination of dietary components after the patients'initial successful treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA137765-02
Application #
7888328
Study Section
Special Emphasis Panel (ZCA1-SRLB-F (M1))
Program Officer
Riscuta, Gabriela
Project Start
2009-07-08
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$67,500
Indirect Cost
Name
Clarian Health Partners, Inc.
Department
Type
DUNS #
965248321
City
Indianapolis
State
IN
Country
United States
Zip Code
46206