Table 2.
Treatments for induction of ferroptosis in lung cancer.
| Treatment | Cancer type | Target genes | Model | Description | Ref. |
|---|---|---|---|---|---|
| Chemotherapy: | |||||
| Erastin | NSCLC | ↑p53/↓SCL7A11 | In vitro | * “Erastin-induced ROS lead to the DNA damage response and stimulate p53 in A549 cells” * “Expression of p53 induced by erastin exposure contributes to the cytotoxic effect on A549 cells, leading to ferroptotic and apoptotic death.” * “p53 induced by erastin exposure exerts cytostatic effects on A549 cells” |
(99) |
| Cisplatin | NSCLC | ↓GSH-GPXs | In vitro | * “Cisplatin induced both ferroptosis and apoptosis in A549 cells” * “Silencing iron-responsive element binding protein 2 (IREB2) partially reversed the cytotoxicity of cisplatin, indicating the involvement of iron in cisplatin induced cell death” * “Additive effect observed in combination therapy of cisplatin and erastin” |
(100) |
| Cisplatin (CDDP) with PRLX93936 |
NSCLC | ↓GPX4 | In vitro | * “Nrf2/Keap1 regulates sensitivity to RPLX93936/cisplatin in NSCLC cells.” * “Ferroptosis inhibitors and forced expression of GPX4 attenuated cell death caused by cisplatin and PRLX93936.” |
(101) |
| Vorinostat with erastin | EGFR mutant LUAD | ↓ xCT | In vitro | * “Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers.” * “Cells with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers.” |
(102) |
| Brusatol and erastin | NSCLC | ↓ NRF2 ↑FOCAD-FAK |
In vitro/in vivo | * “Treatment with NRF2 inhibitor, brusatol, increased the sensitivity of NSCLC cells to erastin-induced ferroptosis in vitro and in vivo, which depended on the upregulation of FOCAD partially” * “Brusatol can enhance the efficacy of chemotherapy via inhibiting NRF2 signaling pathway” |
(34) |
| Erastin with acetaminophen (APAP) | NSCLC | ↓NRF2/HO-1 | In vitro/in vivo | * “Combination of erastin and APAP inhibited cell proliferation and induced ferroptosis” * Erastin and/OR APAP regulated intracellular ferrous iron * Erastin and/or APAP‐induced cell death via overgeneration of lipid peroxidation |
(103) |
| Sorafenib combined with erastin | NSCLCs resistant to CDDP | ↓ Nrf2/xCT | In vitro/in vivo | * “Sensitivity of NSCLC cells to CDDP is negatively associated with Nrf2 pathway activation” * “Erastin and sorafenib effectively induce ferroptosis in CDDP resistance cells by inhibiting the Nrf2/xCT pathway” * “Erastin/sorafenib restrains in vivo tumour growth in nude mice xenograft models” |
(104) |
| Siramesine with lapatinib | LUAD | ↓ HO-1 | In vitro | * “Lapatinib and siramesine induce synergistic cell death in lung adenocarcinoma” * “Lapatinib and siramesine treatment increased reactive iron, ROS, and induced ferroptosis through decreasing heme oxygenase-1 (HO-1) protein expression.” * “Decrease in HO-1 expression was due to proteasome degradation and confirms that Nrf2 is not implicated in the regulation of HO-1” |
(57) |
| Levobupivacaine (local anesthetic) and erastin | NSCLC | ↑p53-↓SLC7A11-↓GPX4 | In vitro/in vivo | * “Levobupivacaine inhibits proliferation and promotes apoptosis of NSCLC cells and represses invasion and migration of NSCLC cells.” * “Levobupivacaine induces ferroptosis of NSCLC cells” |
(105) |
| Auranofin (AF, an antirheumatic drug) | NSCLC | ↓TrxR ↓GPX4 ↑ HMOX1 |
In vitro/in vivo | * “p53 R273H cells were more vulnerable to AF-induced ferroptotic cell death due to downregulation of GPX4 and lipid peroxidation.” * “AF primes mutant p53 NSCLC cells for IL-15-stimulated NK cell mediated killing.” * “Contrary, it was observed that mutant p53 was no limiting factor in the activation of NRF2 and GSH levels, despite reduced expression of SLC7A11 in the mutant p53 NCI–H1299 cells” * “To overcome the toxicity of AF-mediated TrxR inhibition, the data showed that all mutant p53 NSCLC cells first boosted their antioxidant defense capacities by upregulation of pro-survival molecules, such as NRF2 and GSH, to maintain their redox balance” |
(106) |
| Natural product therapy: | |||||
| Artemisinin derivatives: Artesunate (ART) and Dihydroartemisinin (DHA) |
NSCLC | ↓VDAC and xCT ↑TFRC |
In vitro | * “Artemisinin derivatives induce apoptosis and ferroptosis.” * “ROS is a key regulator of ART/DHA-induced apoptosis and ferroptosis” * “TFRC and VDAC were closely associated with the survival of lung cancer patients and can be used as potential therapeutic targets in lung cancer.” |
(107) |
| Dihydroisotanshinone I (DT) | NSCLC | ↓GPX4 | In vitro and in vivo | * “DT inhibited the growth of lung cancer cells through apoptosis and ferroptosis and in vivo study inhibited metastasis of A549 cells in the nude mice model.” | (108) |
| Cryptotanshinone (CTN) | NSCLC | ↓GPX4 | In vitro | * “Cryptotanshinone induces ROS generation and caspase activity in lung cancer cell lines” * “CTN induces the lipid peroxidation iron-dependent” * “CTN induces apoptosis to the lower level than ferroptosis” |
(109) |
| Curcumin | NSCLC | ↑ACSL4 ↓ SLC7A11 ↓ GPX4 |
In vivo and in vitro | * ‘Curcumin inhibits tumor growth and promotes cells death in vivo” * “Curcumin suppresses cell proliferation and promotes cell death in vitro” * “Curcumin induces characteristic changes of ferroptosis in mice” * “Inhibition of autophagy attenuated curcumin-induced ferroptosis in A549 and H1299 cells” |
(61) |
| Sulforaphane (SFN) |
SCLC | ↓SLC7A11 | in vitro | * SFN inhibits growth and induces cell death in the SCLC cells * “SFN exhibits anticancer effects against SCLC cells via induction of ferroptosis” * “SFN-induced cell death was mediated via ferroptosis and inhibition of the mRNA and protein expression levels of SLC7A11” |
(110) |
| 6-Gingerol | Lung cancer | ↓USP14 ↓GPX4 ↓ATF4 ↑NCOA4 and TfR1 |
In vitro and in vivo | * “6-Gingerol suppresses tumor growth and enhances the accumulation of ROS and iron.” * “6-Gingerol regulates the expression of autophagy and ferroptosis related proteins in vivo and in vitro.” |
(60) |
| Ginkgetin with cisplatin(DDP) | NSCLC | ↓NRF2/HO-1 axis ↓ GPX4 ↓ SLC7A11 |
In vitro/in vivo | * “Ginkgetin is synergized with DDP to increase cytotoxicity in NSCLC cells.” * “Ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis.” * “Ginkgetin increased labile iron pool and lipid peroxidation and caused elevation of ROS formation, and apoptosis in DDP-treated NSCLC cells.” |
(111) |
| Erianin | Lung cancer | ↑Ca2+/CaM-dependent ferroptosis ↓SLC7A11 |
In vitro/in vivo | * “Erianin triggers cell death, inhibits cell proliferation, migration, and promotes cell cycle arrest in G2/M in lung cancer cells” * “Ferroptosis contributes to erianin-induced cell death in lung cancer cells” * “Erianin results in ferroptosis induction and exerts antitumor efficacy in vivo” |
(64) |
| Food additive for iron supplementation: | |||||
| Ammonium Ferric Citrate (AFC) | NSCLC | ↓GPX4-GSS/GSR-GGT axis | In vitro | * “Decreased the autophagy and cause elevated Fe2+ content and inducing oxidative stress injury consequently ferroptosis.” * “Inhibited the proliferation and invasion of NSCLC cell lines in vitro.” * “Promoted differential gene expression profiles of proliferation and autophagy.” |
(112) |
| Nanoparticle therapy: | |||||
| ZVI-NP (Zero-valent Iron Nanoparticles) | Lung cancer | ↑GSK3β/β-TrCP-dependent degradation of NRF2 | In vitro/in vivo | * “Attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes and caused lipid peroxidation, increased ROS, and ferroptosis.” * “Inhibited NRF2 activity and lung metastases in vivo.” * “ZVI-NP treatment promoted the M1 polarization induction-derived overexpression of TNF-α, while attenuated the expression of the M2 polarization gene DC-SIGN” * “ZVI-NP modulates immune cell profile in mouse model in vivo”. |
(113) |
| Folate (FA)-modified liposome (FA-LP) enriched with erastin and MT1DP (E/M@FA-LPs) | NSCLCs | ↓NRF2 | In vitro/in vivo | * “E/M@FA-LPs sensitizes erastin-induced ferroptosis in vitro.” * “E/M@FA-LPs represses NRF2 levels to enhance oxidative stress.” * “E/M@FA-LPs could powerfully inhibit growth of subcutaneous xenografts.” |
(78) |
| Magnetic field therapy: | |||||
| Magnetic field (MF) therapy concurrent with DDP and PTX treatments | Lung epithelial cancer cells (A549) | – | In vitro/in vivo | * “MF selectively inhibited malignant tumor cells” * “Ferroptosis was detected by co-incubation with ferrostatin-1” * “MF exposure led to ROS-dependent DNA damage and subsequent activation of DNA repair pathways” * “MF induced intracellular oxidative stress” * “MF sensitized tumor cells to conventional chemotherapy(DDP and PTX)” |
(114) |
| Radiation therapy: | |||||
| Radiation combined with IKE and sorafenib | LUAD | ↓ GPX4 ↓xCT |
In vitro/in vivo | * “IKE and sorafenib, combined with stereotactic radiation therapy, suppress tumor growth in a mouse xenograft model of sarcoma and a patient-derived xenograft model of lung adenocarcinoma.” * “Radiation-induced cancer cell death is suppressed by ferroptosis inhibitors” |
(115) |
| Radiation with erastin treatment | NSCLC | ↓GPX4 | In vitro | * “Erastin and IR exhibit a combined effect on killing cells” * “GPX4 expression is increased in the radioresistant cells and erastin inhibits GPX4 expression in the radioresistant cells” * “Knocking down GPX4 expression radiosensitizes NSCLCs cell to radiation in the radioresistant cell lines” |
(116) |
↓, Decreases the expression of; ↑, Increases the expression of.