NRF2-ARE PATHWAYS: DISCOVERY OF NOVEL CHEMOPREVENTIVE COMPOUNDS

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemoprevention is an innovative strategy focusing on the development of pharmacalogical, biological, or nutritional interventions to impede, arrest, or reverse carcinogenesis at various stages in order to prevent and treat cancer. Synthetic or dietary compounds have been explored for chemoprevention. However, potent and safe compounds availalbe in chemopreventive research are very limited. The goal of this proposal is to discover novel and potent compounds, which potentially can be further developed as chemopreventive drugs or biomedical research tools. Phase I cytochrome P450 (CYP) enzymes bioactivate xenobiotics or endobiotics, which often produce highly reactive electrophiles leading to damage of DNA and proteins. Phase II enzymes detoxify the phase I metabolic products. Physiological balance between phase I and II enzyme levels determines the sensitivitiy or risk of an individual exposed to carcinogenic species in cancer development. Therefore, enhancement of phase II detoxifying enzyme activities would be an effective strategy for chemoprevention. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a potent transcription factor. It binds to an antioxidant response element (ARE), which exists in genes encoding many phase II detoxifying enzymes and antioxidant proteins, and plays a vital role in consituitive and inducible expression of these genes. Nrf2 has been recognized as a novel molecular target for chemoprevention. We hypothesize that using a well-identified Nrf2-ARE pathway and a cell-based high throughput screening strategy, potent compounds, which specifically induce phase II detoxifying enzymes and antioxidant proteins, can be discovered and identified. Two specific aims are defined to purse our goal. Specific Aim 1: Identify novel compounds which specifically activate Nrf2-ARE pathway. Specific Aim 2: Evaluate the biological effects of specific Nrf2 activators identified from Specific Aim 1. Discovery and identification of novel, potent, and specific Nrf2 activators will move forward the chemopreventive research by providing new candidates for further development as chemopreventive agents and research tools.