Novel Insights on Ferroptosis Modulation as Potential Strategy for Cancer Treatment: When Nature Kills

Abstract

Significance: The multifactorial nature of the mechanisms implicated in cancer development still represents a major issue for the success of established antitumor therapies. The discovery of ferroptosis, a novel form of programmed cell death distinct from apoptosis, along with the identification of the molecular pathways activated during its execution, has led to the uncovering of novel molecules characterized by ferroptosis-inducing properties. Recent advances: As of today, the ferroptosis-inducing properties of compounds derived from natural sources have been investigated and interesting findings have been reported both in vitro and in vivo. Critical Issues: Despite the efforts made so far, only a limited number of synthetic compounds have been identified as ferroptosis inducers, and their utilization is still limited to basic research. In this review, we analyzed the most important biochemical pathways involved in ferroptosis execution, with particular attention to the newest literature findings on canonical and non-canonical hallmarks, together with mechanisms of action of natural compounds identified as novel ferroptosis inducers. Compounds have been classified based on their chemical structure, and modulation of ferroptosis-related biochemical pathways has been reported. Future Directions: The outcomes herein collected represent a fascinating starting point from which to take hints for future drug discovery studies aimed at identifying ferroptosis-inducing natural compounds for anticancer therapies. Antioxid. Redox Signal. 40, 40-85.

Keywords: anticancer strategies; cancer; ferroptosis; ferroptosis inducers; natural compounds; oxidative stress; phytochemicals.

Color images are available online.

FIG. 1.

Schematic representation of the main signaling pathways involved in ferroptosis. ACSL3, acyl-CoA synthetase long chain family member 3; ACSL4, acyl-CoA synthetase long chain family member 4; ALOX, lipoxygenase; BH4, tetrahydrobiopterin; CISD1, CDGSH Iron Sulfur Domain 1; DPP4, Dipeptidyl-peptidase-4; ESCRT-III, endosomal sorting complex required for transport-III; FPN, ferroportin-1; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase-1; GCLC, glutamate-cysteine ligase catalytic subunit; GPX4, glutathione peroxidase 4; GR, GSH reductase; GSH, glutathione; GSS, GSH synthetase; GSSG, GSH disulfide; HO-1, heme oxygenase-1; LPCAT3, lysophosphatidylcholine acyltransferase 3; MRP1, multidrug resistance protein 1; MUFA, monounsaturated fatty acids; MUFA-CoA, MUFA-acyl-CoA esters; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NCOA4, nuclear receptor coactivator 4; NOX, NADPH oxidase; p53, tumor protein p53; PCBP1, poly (rC)–binding protein 1; PROM2, prominin 2; PUFA, polyunsaturated fatty acid; PUFA-CoA, PUFA-acyl-CoA esters; PUFA-PL, phospholipid PUFA; SAT1, spermidine/spermine N1-acetyltransferase 1; SCD1, stearoyl CoA desaturase 1; STEAP3, six-transmembrane epithelial antigen of the prostate 3; ZIP, ZRT/IRT-like protein. Color images are available online.

FIG. 2.

Representation of the principal xc^‒ system and GPX4 inhibitors. Color images are available online.

FIG. 3.

Schematic representation of cellular iron homeostasis and its impact on the ferroptotic process. CO, carbon monoxide; FT, ferritin; HO, heme oxygenase; TfR1, transferrin receptor 1. Color images are available online.

FIG. 4.

Schematic representation of lipid peroxidation pathways involved in ferroptosis onset. PUFA-PLOOH, PUFA-phospholipid hydroperoxide. Color images are available online.

FIG. 5.

NRF2 activation under oxidative stress conditions leads to its nuclear translocation, where it anchors ARE and heterodimerizes with sMaf proteins for the transcription of several antioxidant genes, resulting in ferroptosis dampening. ARE, antioxidant response element; CUL3, cullin3; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GSK3β, Glycogen Synthase Kinase 3 Beta; Keap1, kelch-like ECH-associated protein 1; MGST1, microsomal glutathione S-transferase 1; NQO1, NAD(P)H Quinone Dehydrogenase 1; NRF2, nuclear factor erythroid 2 (NF-E2)-related factor 2; RBX1, ring box protein 1; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; sMaf, small musculoaponeurotic fibrosarcoma proteins. Color images are available online.

FIG. 6.

GSH homeostasis mediates ferroptosis susceptibility. BSO, buthionine sulfoximine; RSL3, RAS-selective lethal molecule 3. Color images are available online.

FIG. 7.

NADPH as potential ferroptosis marker. MARCHF6, Membrane Associated Ring-CH-Type Finger 6; MESH1, human Metazoan SpoT Homolog 1; Ub, ubiquitin. Color images are available online.

FIG. 8.

GCH1-BH4 axis and FSP1 activity prevent lipid peroxidation and display anti-ferroptotic effects. Color images are available online.

FIG. 9.

Representation of the principal ferroptosis-related factors specific for each type of cancer reported. σ₁R, sigma-1 receptor; ACACA, acetyl-coa carboxylase alpha; AGBL2, AGBL Carboxypeptidase 2; AKR1C1, aldo-keto reductase family 1 member C1; ATP6V1G2, ATPase H+ transporting V1 subunit G2; BCL2, B-cell lymphoma 2; C5orf64, lncRNA Chromosome 5 Putative Open Reading Frame 64; CARS1, Cysteinyl-TRNA Synthetase 1; CASC1, cancer susceptibility candidate 1; CDKN2A, cyclin dependent kinase inhibitor 2A; CDO1, cysteine dioxygenase 1; ELOVL2, elongation of very-long-chain fatty acids-like 2; FDFT1, farnesyl-diphosphate farnesyltransferase 1; FGD3, facio-genital dysplasia 3; G6PD, Glucose-6-Phosphate Dehydrogenase; GDF15, growth differentiation factor 15; HAMP, hepcidin antimicrobial peptide; LINC00968, Long Intergenic Non-Protein Coding RNA 968; LINC01800, Long Intergenic Non-Protein Coding RNA 1800; lncRNA, long noncoding RNA; MT-1G, metallothionein-1G; NFS1, cysteine desulfurase; NOS2, nitric oxide synthase 2; PVT1, lncRNA plasmacytoma variant translocation 1; RRM1, ribonucleotide reductase subunit 1; SEC14L2, SEC14 Like Lipid Binding 2; SERPINA3, Serpin Family A Member 3; SLC1A4, Solute Carrier Family 1 Member 4; SLC1A5, Solute Carrier Family 1 Member 5; SLC39A8, solute carrier family 39 member 8; SUSD3, Sushi Domain Containing 3; TFAP2C, transcription factor AP-2 gamma; TPRG1, Tumor Protein P63 Regulated 1. Color images are available online.