Research Grants Awarded
Novel Natural Products for Breast Cancer Prevention and Treatment
Background: Breast cancer is a major threat to the health and lives of women. Novel approaches are needed for more effective prevention and treatment of the disease. Natural compounds are becoming more widely recognized for their anti-cancer potential: most chemopreventive agents and many chemicals currently used for chemotherapy have been derived from of natural sources or are derivatives of natural compounds. Recently, we have identified and purified, from Panax notoginseng, a novel natural compound, 25-methoxyprotopanaxadiol (25-OCH3-PPD). This compound has potent cytotoxic and pro-apoptotic effects in breast cancer cell lines and modifies the expression of several proteins, MDM2, p21, p27, and E2F1, which are involved in the initiation, progression, and treatment of cancer. 25-OCH3-PPD substantially decreases expression of MDM2, an oncoprotein that functions as a key regulator of apoptosis, proliferation, and the cell cycle through its interactions with proteins such as p53, p21, E2F1. Objective: The long-term objectives of the proposed research are to demonstrate that 25-OCH3-PPD represents a novel anti-cancer agent for both of cancer prevention and treatment and to elucidate its primary mechanism of action. Specific Aims: We propose the following: 1) To demonstrate that 25-OCH3-PPD prevents the development of breast cancer; 2) To demonstrate the therapeutic effects of 25-OCH3-PPD in models of breast cancer, both as monotherapy and in combination with conventional therapies; and 3) To determine the mechanisms by which 25-OCH3-PPD regulates MDM2 in breast cancer. Potential Outcomes and Benefits: Completion of these specific aims will provide the basis for further preclinical and clinical evaluations of this chemical and related natural compounds for breast cancer prevention and therapy. Additionally, knowledge gained in our mechanistic studies will lead to a better understanding of drug-gene interactions in carcinogenesis and treatment of breast cancer and provide a new avenue of basic and translational research in this disease.
Breast cancer is one of the most common cancers, and it is estimated that more than 41,000 women will die of the disease this year. Despite the fact that there have been some advances made in diagnosing and treating breast cancer, the mortality rate is still high. Conventional chemotherapy often has severe side effects, and more rationally-targeted therapies (e.g., Herceptin® or tamoxifen) are effective only for certain populations of cancer patients. New approaches are urgently needed to prevent and treat breast cancer. Recently, we have identified and purified a novel natural compound from Panax notoginseng, called 25-OCH3-PPD. We discovered that this compound prevented the growth, inhibited the division, and increased the death of human breast cancer cells that were either estrogen receptor-positive and -negative. This compound also modifies the expression of several proteins, such as MDM2, p21, p27, and E2F1, which are known to be involved in the initiation, progression, and treatment of cancer. It substantially decreased expression of MDM2, a protein that functions as a key regulator of apoptosis, proliferation, cell cycle through its interactions with other proteins, including p53, p21, E2F1. Based upon these observations, we propose to determine if the compound has preventive and therapeutic effects in animal models of human breast cancer. We will also establish how the compound works, focusing on its effects on the expression of proteins that are involved in cancer development and treatment. The anticipated results should lead to further preclinical and clinical testing of this compound as a new approach to prevention and therapy of breast cancer. Knowledge gained in the proposed mechanistic studies will also lead to a better understanding of drug-gene interactions in cancer formation and treatment and provide a new avenue to explore basic and translational researches in breast cancer.