A Novel Nrf2 Pathway Inhibitor Sensitizes Keap1-Mutant Lung Cancer Cells to Chemotherapy

Abstract

The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo. Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

Exploring structural effects in a new class of NRF2 inhibitors

“…To monitor NRF2 inhibition activities, a standardized luciferase assay with standard errors calculated based on multiple runs was employed. 20 To achieve these goals, a variety of different catalytic methods were brought to bear including titanium multicomponent, palladium, and copper coupling reactions. In some cases, further modifications were made, including protection/deprotection and hydrogenation.…”

“…19 In a recent publication, the Liby and Odom laboratories reported the discovery of a novel NRF2 pathway inhibitor, the small molecule MSU38225, which was effective in vivo and in vitro. 20 The compound showed promising selectivity for the NRF2 pathway and did not alter the concentrations of common off-target cellular proteins. Cells with constitutive NRF2-activity (KEAP1 mutant) were more sensitive than wildtype cells to the compound.…”

The mechanism of Bai He Gu Jin Tang against non-small cell lung cancer revealed by network pharmacology and molecular docking

“…[ 55 ] The down-regulation of AKR1C2 could sensitize keap1-mutant NSCLC cells to chemotherapy. [ 56 ]…”

Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer

“…At the same time, Nrf2 is overexpressed in different tumor types [ 136 , 137 ] and can promote tumor growth and metastasis [ 138 ]. Furthermore, Nrf2 promoted cancer chemoresistance by stimulating the expression of ARE-dependent multidrug resistance genes and decreased the effectiveness of common chemotherapies such as doxorubicin, carboplatin, or cisplatin [ 139 , 140 ]. Importantly, Nrf2 is a central regulator of MDSC number and function.…”