Effect of Nrf2 in tumor progression and its inhibitors in cancer therapy / 中国中药杂志

Nrf2 is the key transcription factor mainly for regulating oxidative homeostasis and cytoprotective responses against oxidative stress. Nrf2/Keap1 pathway is one of the most important cellular defense mechanisms against endogenous or exogenous oxidative stress. With its activation, a wide range of stress-related genes is transactivated to restore the cellular homeostasis. Recent studies revealed that the aberrant activation of Nrf2 is related to the malignant progression, chemotherapeutic drug resistance and poor prognosis. Nrf2 plays a crucial role in cancer malignancy and chemotherapeutic resistance by controlling the intracellular redox homeostasis through the activation of cytoprotective antioxidant genes. Nrf2 inhibitor containing many natural products has been deemed as a novel therapeutic strategy for human malignancies. This article reviews the progress of studies of the Nrf2/Keap1 pathway, and its biological impact in solid malignancies and molecular mechanisms for causing Nrf2 hyperactivation in cancer cells. In conclusion, we summarized the deve-lopment of Nrf2 inhibitors in recent years, in the expectation of providing reference for further drug development and clinical studies.

Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.