Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment

Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates redox homeostasis, plays a pivotal role in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. As one of the key oncogenes, Nrf2 represents an important therapeutic target for cancer treatment. Research has unraveled the main mechanisms underlying the Nrf2 pathway regulation and the role of Nrf2 in promoting tumorigenesis. Many efforts have been made to develop potent Nrf2 inhibitors, and several clinical trials are being conducted on some of these inhibitors. Natural products are well-recognized as a valuable source for development of novel therapeutics for cancer. So far, a number of natural compounds have been identified as Nrf2 inhibitors, such as apigenin, luteolin, and quassinoids compounds including brusatol and brucein D. These Nrf2 inhibitors have been found to mediate an oxidant response and display therapeutic effects in different types of human cancers. In this article, we reviewed the structure and function of the Nrf2/Keap1 system and the development of natural Nrf2 inhibitors with an emphasis on their biological function on cancer. The current status regarding the Nrf2 as a potential therapeutic target for cancer treatment was also summarized. It is hoped that this review will stimulate research on naturally occurring Nrf2 inhibitors as therapeutic candidates for cancer treatment.