Acetaminophen sensitizing erastin‐induced ferroptosis via modulation of Nrf2/heme oxygenase‐1 signaling pathway in non‐small‐cell lung cancer

Gai, Chengcheng; Yu, Mengyu; Li, Zihaoran; Wang, Yonghong; Ding, Dejun; Zheng, Jie; Lv, Shijun; Zhang, Weifen; Li, Wentong

doi:10.1002/jcp.29221

Cited by 106 publications

(58 citation statements)

References 34 publications

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“…The Nrf2-mediated defensive response can effectively protect cells and tissues against toxins, oxidants, and drugs 47 . Inhibition of the Nrf2 pathway has been reported to increase ferroptosis sensitivity 48 . Several chemical Nrf2 activators have demonstrated the protective effects against APAP-induced hepatotoxicity 49,50 .…”

Section: Discussionmentioning

confidence: 99%

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

Wang

Liu

et al. 2020

Cell Death Dis

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Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1–Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.

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Section: Discussionmentioning

confidence: 99%

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

Wang

Liu

et al. 2020

Cell Death Dis

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“…1a). Our previous studies have demonstrated that A549 and H1299 cells are insensitive to ferroptosis induced by erastin 17 , so we tested the effect of erastin on MT1DP expression. Our results found that MT1DP expression in NSCLC cells treated with erastin decreased (Fig.…”

Section: Mt1dp Sensitizes Erastin-induced Ferroptosis Via Repressingmentioning

confidence: 99%

MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells

et al. 2020

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Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/MT1DP@FA-LPs (E/M@FA-LPs) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/M@FA-LPs had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.

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“…A common feature of ferroptosis is endogenous lipid peroxidation. [29] MDA, a prouduct of lipid peroxidation [30], was investigated to assess the degree of ferroptosis. Results showed TA-Fe/ART@ZIF nanoparticles produced approximately 2.5 times higher MDA levels than control group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fe(II) and tannic acid-cloake MOF as carrier of artemisinin for supply of ferrous ions to enhance treatment of triple-negative breast cancer

Wang

et al. 2020

Preprint

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Suppression of tumor development by inducing ferroptosis may provide a potential remedy for triple-negative breast cancer (TNBC), which is sensitive to intracellular oxidative imbalance. Recently, artemisinin (ART) and its derivatives have been investigated as potential anticancer agents for the treatment of highly aggressive cancers via the induction of ferroptosis by iron-mediated cleavage of the endoperoxide bridge. Poor water solubility and insufficient availability of intracellular ferrous ions, limit the further application of ART in antitumor therapy. In this study, ferrous-supply nanocarrier was constructed based on tannic acid (TA) and ferrous ion (Fe2+)-coated on the zeolitic imidazolate framework-8(ZIF) with ART encapsulated (TA-Fe/ART@ZIF). via supramolecular coordination. Following the internalization of the as-prepared nano-system in cells, acidic degradation of the vehicles would facilitate the release of ART and accumulation of Fe2+. The results revealed that the newly developed nano-drug system displayed a high level of intracellular ROS generation, and markedly enhanced ferroptosis. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine and new directions for TBNC therapy.

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Acetaminophen sensitizing erastin‐induced ferroptosis via modulation of Nrf2/heme oxygenase‐1 signaling pathway in non‐small‐cell lung cancer

Cited by 106 publications

References 34 publications

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis

MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells

Fe(II) and tannic acid-cloake MOF as carrier of artemisinin for supply of ferrous ions to enhance treatment of triple-negative breast cancer

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