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Table 3 Summary of compounds targeting Keap1-Nrf2 pathway and their mechanisms of action

From: Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review

Compounds Mechanisms of action In vitro activity In vivo activity Refs
Nrf2 activators
Esculetin Binds to Keap1, disrupts Keap1-Nrf2 interaction, and activates Nrf2 Inhibits cell growth, arrests cells at G1 phase, and induces cell apoptosis NR [109]
MT477 Activates Nrf2 signaling pathway Inhibits cell survival Suppresses tumor growth in MiaPaca-2 xenograft model [16]
Oleanolic acid (OA) Activates ERK/Nrf2 signaling pathway Suppression of ERK/Nrf2 pathways strengthens OA-induced apoptosis Suppression of ERK/Nrf2 pathways enhances OA’s efficacy in a xenograft model [45]
Fisetin Activates Nrf2 signaling pathway Inhibits cell growth NR [110]
QD325 Induces substantial ROS and activates Nrf2 signaling pathway Inhibits cell growth Suppresses tumor growth and enhances the efficacy of gemcitabine in MiaPaca-2 xenograft model [17]
Resveratrol Increases the expression and activity of Nrf2 and decreases the expression of NAF-1 Inhibits cell growth, induces cell apoptosis, and enhances cell sensitivity to gemcitabine NR [61]
Sulforaphane Increases the expression and activity of Nrf2 through activating AMPK Inhibits cell growth and invasion Suppresses tumor growth in Panc-1 xenograft model and a transgenic pancreatic cancer mouse [90]
Alphalipoic acid Increases the expression and activity of Nrf2 NR Suppresses tumor growth in CFPAC-1 xenograft model [111]
Nrf2 inhibitors
Brusatol Inhibits Nrf2 expression and activity and increases ROS accumulation Enhances growth inhibition and apoptosis caused by gemcitabine Suppresses tumor growth and enhances the efficacy of gemcitabine in Panc-1 xenograft model [112]
Digoxin Decreases Nrf2 mRNA level through inhibiting PI3K/Akt pathway Enhances growth inhibition and apoptosis caused by gemcitabine Sensitizes SW1990/Gem cells-derived xenografts to gemcitabine [19]
PIK-75 Induces Nrf2 proteasomal degradation Inhibits cell proliferation and survival and potentiates gemcitabine- induced cytotoxicity Suppresses tumor growth and enhances the efficacy of gemcitabine in MiaPaca-2 xenograft model [18]
Clobetasol propionate (CP) Prevents Nrf2 nuclear accumulation and induces its degradation Inhibits growth of cancer cells with mutations in Keap1 or both in Keap1 and LKB1 alone or in combination with rapamycin Suppresses growth of tumors containing mutations in both Keap1 and LKB1 alone or in combination with rapamycin [113]
ML385 Directly binds to the CNC-bZIP domain of Nrf2 and inhibits its DNA binding activity Exerts selective cytotoxicity against cancer cells with Keap1 mutations alone or in combination with carboplatin Suppresses growth of tumors with Keap1 mutations alone or in combination with carboplatin [114]
AEM1 Inhibits Nrf2 transcriptional activity Inhibits the growth of cancer cells harboring mutant Keap1 alone or in combination with chemotherapy Suppresses growth of tumors harboring Keap1 mutations [115]
Pterostilbene Inhibits Nrf2 nuclear translocation and activity Inhibits cell viability Suppresses tumor growth in AsPC-1 xenograft model [116]
  1. NR, Not reported