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.

Analysis of Healthcare Personnel's Clinical Beliefs and Knowledge behind Overutilization of Stress Ulcer Prophylaxis in Hospitalized Patients

BACKGROUND: The over-prescription of acid-suppressive therapy for the provision of stress ulcer prophylaxis (SUP) in hospitalized patients has been identified in a proceeding study. OBJECTIVE: This study was conducted to evaluate clinicians' beliefs, knowledge and other factors that influence the over-prescribing of SUP in low-risk, non-intensive care unit (non-ICU) patients. METHOD: A cross-sectional survey consisting of multiple-choice queries and close-ended questions was distributed to healthcare personnel at a major teaching hospital in Korea. RESULTS: More than half of total respondents reported that they would continue SUP following patients discharge from the ICU (77.8%, 43.5%, and 39.7% in the physician, pharmacist, and nurse groups, respectively). Over 55% of physicians would also initiate non-ICU patients on SUP upon hospital admission, and 42.6% of physicians would even continue prophylaxis post hospital discharge. The mean knowledge score regarding SUP indications and side effects was higher in pharmacists compared to physicians and nurses (12.44, 7.40, and 7.28, respectively; p<0.001). High-prescribing behavior was associated with a prescriber's belief that SUP is effective for preventing bleeding (odds ratio 7.40; 95% confidence interval 1.57 to 31.94; p=0.012). Low knowledge score and computerized order set also showed statistically significant association with the overutilization of SUP.