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] |