Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes, which produce proteins responsible for the detoxification of chemical carcinogens and the suppression of reactive oxygen species. Under basal conditions, Nrf2 is constantly degraded via the ubiquitin-proteasome pathway in a Kelch like ECH-associated protein 1 (Keap1)-dependent manner. Upon exposure to electrophilic and oxidative stresses, Nrf2 is able to escape Keap1-mediated repression, translocate into the nucleus, and activate the expression of its target genes. It is widely accepted that the induction of Nrf2-regulated enzymes results in protection against massive oxidative stress and chemical carcinogenesis. Nrf2 activators are developed as putative chemopreventive agents. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations are reported to result in permanent Nrf2 activation, leading to overexpression of cytoprotective enzymes. Constitutive induction of Nrf2-regulated enzymes can confer multiple advantages on cancer cells for their proliferation and resistance to chemotherapy. Suppression of abnormal Nrf2 activation is needed, therefore, for a new therapeutic approach against tumors resistant to cytotoxic action of anticancer drugs. However, there is little research to identify Nrf2 inducers and inhibitors from crude drugs. In this article, we investigated whether Nrf2 activity in mammalian cells was enhanced or suppressed by treatment with crude drugs and how modulation of Nrf2-reuglated enzymes by crude drugs affected cytotoxic action of chemical compounds.
