Research Grants Awarded
Mechanisms of breast cancer-preventive effects of organosulfur compounds
RISK and Prevention, Epidemiology
Background: Epidemiological studies continue to support the premise that increased consumption of allium vegetables, such as garlic, may be protective against the risk of certain types of cancers including breast cancer. Recent studies have revealed that human breast cancer cells are highly sensitive to growth inhibition by diallyl trisulfide (DATS), a garlic-derived organosulfur compound (OSC). Interestingly, viability of a normal breast epithelial cell line (MCF-10A) was minimally affected by DATS even at concentrations that were highly cytotoxic to the breast cancer cells. These results are encouraging since selective killing of cancer cells is a highly desirable property of potential cancer preventive/therapeutic agents. Objective/Hypothesis: The underlying hypothesis driving this project is that DATS elevates the intracellular level of reactive oxygen species (ROS) and subsequently activates JNK and caspases. The activation of the apoptotic pathway leads to the chemopreventive efficacy of DATS. Specific Aims: The specific aims of this project are to examine (1) whether DATS elevates the intracellular level of ROS by either increasing production of ROS through the mitochondrial electron transport chain or decreasing elimination of ROS through the glutathione peroxidase/glutathione reductase system, (2) whether redox-regulatory proteins such as thioredoxin (TRX) and glutaredoxin (GRX) recognize DATS-induced oxidative stress and activate the ASK1-MEK-JNK-Bim-Bax signal transduction pathway, and (3) whether intrinsic and extrinsic caspase pathways are involved in DATS-induced apoptotic death. Study design: In the proposed studies, the first aim will use a spectrofluorometer to measure the intracellular level of ROS. The second aim will be use biochemical assays to investigate the ASK1-MEK-JNK signal transduction pathway. The third aim will use pharmacological and molecular genetic approaches to attenuate the activity/expression of caspase. Potential Outcomes and Benefits of the Research: We believe that the successful outcome of this study will support the development and clinical application of DATS for the chemoprevention of human breast cancer.
Cancer is now the leading cause of death for Americans under the age of 85, surpassing deaths from heart disease. In 2002, the most recent year for which statistics are available, 476,009 Americans under 85 died of cancer, compared to 450,637 who died of heart disease, according to the American Cancer Society’s annual report. Among cancers, breast cancer has become the most frequently diagnosed cancer among women in the United States, and the second leading cause of cancer related deaths. Early diagnosis with mammography, advanced local and systemic adjuvant therapies, and improvement of surgical techniques have contributed to enhanced survival of breast cancer patients. However, when breast cancer becomes metastasized to the lung, liver, brain, or adrenal gland, it is difficult to cure. Thus, clinical development of chemoprevention agents that are non-toxic to normal tissue but can inhibit or delay onset and progression of breast cancer could have a significant impact on incidence of this deadly disease. Recent studies have shown that the risk of breast cancer was significantly low in women consuming more than 20 g/day of total allium vegetables (e.g. garlic, onion, chives, leeks, etc.) in comparison to those with low total allium vegetable intake. The reduced risk of breast cancer associated with allium vegetable intake was shown to be independent of body size, intake of other foods, and total calorie intake. Diallyl trisulfide (DATS), a garlic-derived organosulfur compound (OSC), is a constituent of several allium vegetables. Our recent studies have demonstrated that DATS, among OSC analogues, effectively inhibits breast cancer cell proliferation and causes cancer cell death, but causes minimal toxicity to normal cells. In this study, we will determine the mechanism of DATS-induced breast cancer cell death, and the effect of DATS on breast tumor growth and breast tumorigenesis. We believe that this study will provide information to improve the chemopreventive efficacy of DATS against breast cancer.