A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations

Simple Summary Glioblastoma (GBM) is the most common and deadliest brain tumor. Currently, there is no successful treatment available for GBM patients. Different genes are mutated in GBM tumors, including the tumor suppressor p53 gene. Another important gene responsible for cellular homeostasis is Nrf2, which is upregulated in GBM. In this study, we investigate a set of Nrf2 inhibitors and activators identified from a library of small molecules for their roles in enhancing treatment outcome, and to understand the interplay between p53 and Nrf2 in GBM. We studied GBM cells genetically engineered to express clinically important mutants of p53. We were able to identify an Nrf2 inhibitor that significantly reduces cell growth and increases cellular apoptosis in GBM cells. We observed a synergistic therapeutic effect of combined Nrf2 inhibitor and chemotherapeutic drug temozolomide. Abstract TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2–related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.