Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…Increased overall ROS level and mitochondrial ROS level, lipid peroxidation, GSH depletion, decreased GPX4 and ATP level, inhibited by DFO, Fer-1, GSH or NAC [100,105] HEP-2, 5-8F, CNE-1, CNE-2, CNE-2Z; [100] HL-60, KG1, THP-1 [105] HL-60 [105] Nonthermal plasma Reduce Fe 3+ in ferritin to generate Fe 2+ Lipid peroxidation, inhibited by DFO [141] Mesothelioma [141] NA Siramesine+ lapatinib Increase iron level by up-regulation of transferrin and down regulation of ferroportin-1 ROS accumulation, increased iron level, inhibited by DFO or Fer-1 [142] MDA MB 231, MCF-7, ZR-75, SKBr3 [142] NA Salinomycin, (ironomycin) Block iron translocation and deplete ferritin Lipid peroxidation, inhibited by DFO, Fer-1 or NAC [78,143] HMLER CD24 low (CSCs) [78] MCF-7 [78] FINO2 Oxidize ferrous iron and lipidome directly, inactivate GPX4 indirectly Lipid peroxidation, inhibited by β-ME or Fer-1 [97] HT-1080; [97] RS4;11 [98] NA BAY 11-7085 Upregulation of HMOX1 ROS accumulation, lipid peroxidation, GSH depletion, inhibited by Fer-1, Lip-1 or NAC [68] MDA-MB-231, MDAMB-468, MCF-7, SKBR3, A549, HuH-7, DBTRG-05MG, SKOV3 [68] NA Trigonelline Inhibit NRF2 Reverse inhibitory effect of HNC cells on RSL-3 [144] AMC-HN2-11, HN3R, HN3-rslR [144] NA CIL41, 56, 69, 70, 75 and 79 Unknown Lipid peroxidation, inhibited by α-Toc or DFO. (CIL56 induces ferroptosis at lower concentration, and induce nonsuppressible necrotic death at higher concentrations) [96] HT-1080, BJeH, BJeHLT, DRD, and BJeLR [96] NA Ferroptocide Inhibit antioxidant thioredoxin and modulate immune system positively ROS accumulation, lipid peroxidation, inhibited by Trolox, Fer-1 or DFO [99] ES-2, HCT 116, 4T1, A549, U937, MIA PaCa-2, BT-549, T47D, MDA-MB-231, 4T1 and primary cancer cells from patients (lung, ovarian, primary peritoneal carcinomatosis [99] 4T1 [99] Nanoparticles C′ dots+amino acid starvation Recruit and deliver iron into cells Lipid peroxidation, GSH depletion, inhibited by Trolox, Lip-1, Fer-1, DFO, BHA or V C [114] M21, BxPC3, H1650, HT-1080 [114] 786-O, HT-1080…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…A study recently found that ferroptosis inducers RSL3 and ML-162 induce ER stress via the PKR-like ER kinase (PERK)-ATF4-SESN2 pathway and subsequently induce p62 expression. p62 further inactivates Keap1, and Nrf2 was activated by p62-Keap1 interaction, and the ARE associated with iron and antioxidant systems was increased at the same time, resulting in LIP reduction (Shin et al, 2018). Exposure of astrocytes to Fe2 + resulted in increased Nrf2 time-and concentrationdependent expression, whereas knockdown of Nrf2 levels by siRNA resulted in greater toxicity of Fe2 + -induced astrocytes (Cui et al, 2016).…”

“…The activity of Nrf2 is strictly regulated by Kelch-like ECH-related protein 1 (Keap1); Keap1 not only passively isolates Nrf2 from the cytoplasm but also plays an active role in targeting Nrf2 for ubiquitination and proteasome degradation (Zhang et al, 2004;Furukawa and Xiong, 2005). Nrf2 can directly or indirectly regulate GPX4 protein content (Hayes and Dinkova-Kostova, 2014;Fan et al, 2017;Dodson et al, 2019;Zhang et al, 2019), intracellular free iron content (Agyeman et al, 2012;Sun et al, 2016b;Shin et al, 2018), mitochondrial function (Merry and Ristow, 2016;Navarro et al, 2017), nicotinamide adenine dinucleotide hydro-phosphoric acid (NAPDH) regeneration (Abdalkader et al, 2018), etc., thereby regulating ferroptosis process. Of note, many studies found that Nrf2 is expressed in the central nervous system (CNS), neurons, astrocytes, leukocytes, and microglia (Tanaka et al, 2011;Dang et al, 2012;Sandberg et al, 2014), and numerous evidence suggests that Nrf2 plays an important role in the development and treatment of neurodegenerative diseases Deng et al, 2019;Jang et al, 2019;Pachón-Angona et al, 2019;Wei et al, 2019).…”

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Remarkably, the effect was restricted to Artesunate-or Cisplatin-resistant HNC cells, sparing normal oral keratinocytes and oral fibroblasts [301]. Lately, the same group reported that in HNC cells, suppression of NRF2 signaling by Trigonelline could reverse the resistance to ferroptosis both in vitro and in vivo [335]. Thus, Trigonelline is emerging as a promising molecule for combination regimens against tumors with widespread chemoresistance.…”