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Natural products targeting ferroptosis pathways in cancer therapy (Review)

  • Authors:
    • Xin Na
    • Lin Li
    • Dongmei Liu
    • Jiaqi He
    • Ling Zhang
    • Yiping Zhou
  • View Affiliations

  • Published online on: July 23, 2024     https://doi.org/10.3892/or.2024.8782
  • Article Number: 123
  • Copyright: © Na et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ferroptosis inducers (FIN) have a key role in cancer therapy and provide novel and innovative treatment strategies. Although many researchers have performed FIN screening of synthetic compounds, studies on the identification of FIN from natural products are limited, particularly in the field of drug development and combination therapy. In this review, this gap was addressed by comprehensively summarizing recent studies on ferroptosis. The causes of ferroptosis were categorized into driving and defensive factors, elucidating key pathways and targets. Next, through summarizing research on natural products that induce ferroptosis, the study elaborated in detail on the natural products that have FIN functions. Their discovery and development were also described and insight for clinical drug development was provided. In addition, the mechanisms of action were analyzed and potential combination therapies, resistance reversal and structural enhancements were presented. By highlighting the potential of natural products in inducing ferroptosis for cancer treatment, this review may serve as a reference for utilizing these compounds against cancer. It not only showed the significance of natural products but may also promote further investigation into their therapeutic effects, thus encouraging research in this field.

Introduction

Ferroptosis in cancer treatment

Cancer is a primary contributor to global mortality and existing cancer treatment methods generally have restricted effectiveness along with substantial side effects. Hence, safer and more efficient cancer treatment techniques need to be developed. Several studies have highlighted the relationship between ferroptosis and the progression of various diseases, particularly its role in cancer therapy (1,2). Stockwell et al (2) proposed that triggering ferroptosis is an effective strategy in cancer treatment, particularly for treating mesenchymal and metastatic cancers, which are generally resistant to conventional therapeutic techniques. In 2012, Dixon et al (3) coined the term ‘ferroptosis’, which is an iron-dependent mechanism of cell death caused by lipid peroxide overload in the cell membrane.

The mechanism of cell death due to ferroptosis differs significantly from the mechanism of cell death caused by necrosis, autophagy and apoptosis in terms of cellular morphology, genetics and biology. For instance, in terms of differences in morphological characteristics, cells undergoing ferroptosis lack the typical apoptotic characteristics but instead display shrunken mitochondria and a decrease in the number of mitochondrial cristae. The accumulation of lethal lipid peroxides is an important characteristic of ferroptosis, involving a conflict between systems that promote and inhibit ferroptosis. Ferroptosis occurs when the pro-ferroptotic mechanisms driving cellular processes exceed the antioxidant buffering capacity provided by the ferroptosis defense systems (47). Inducing ferroptosis is a promising cancer treatment strategy. Further studies in this area can lead to the development of new and effective cancer treatment techniques. The driving and inhibitory factors of ferroptosis determine whether ferroptosis will occur. Ferroptosis inducers (FIN) can promote the driving factors of ferroptosis or weaken the inhibitory factors to induce ferroptosis. The mechanisms that drive and inhibit ferroptosis are shown in Fig. 1.

Figure 1.

Ferroptosis-driving and ferroptosis defense mechanisms. T The entire Fig. 1. shows the complete cell, with the left side representing the driving factors and organelles of ferroptosis, and the right side representing the defense factors of ferroptosis, all of which act on the middle cell membrane. They occur within cells and ultimately act on cell membranes. PUFA-PLs are synthesized by ACSL4 and LPCAT3 and are prone to peroxidation via non-enzymatic (Fenton reaction) and enzymatic (ALOXs, POR) mechanisms, with iron as a catalyst. Mitochondrial metabolism also generates ROS, ATP and/or PUFA-PLs. Excess lipid peroxides on cell membranes can trigger ferroptosis. Four pathways defend against ferroptosis: The Cyst(e)ine/GSH/GPX4 axis, FSP1-CoQ10-NAD(P)H axis, GCH1/BH4 axis and DHODH/CoQH2 axis. GPX4, in the first pathway, reduces lipid peroxides via a GSH-dependent mechanism, serving as a classic defense against ferroptosis. ACSL4, acyl-coenzyme A synthetase long chain family member 4; ALOXS, lysophosphatidylcholine acyltransferase 3 arachidonate lipoxygenases; GPX4, GSH peroxidase 4; GSH, glutathione; FSP1, ferroptosis suppressor protein 1; CoQ, ubiquinone; CoQH2, reduced ubiquinone; DHODH, dihydroorotate dehydrogenase; GCH1, GTP cyclohydrolase 1; BH4, tetrahydrobiopterin; LPCAT3, lysophosphatidylcholine acyltransferase 3; POR, cytochrome P450 oxidoreductase; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; NADPH, nicotinamide adenine dinucleotide phosphate; FNM, flavin mononucleotide; PRPP, phosphoribosyl pyrophosphate; OA, orotate; PUFA-PL, polyunsaturated fatty acid-containing phospholipid.

Driving factors of ferroptosis: Lipid metabolism

Lipid peroxidation in the cell membrane is a key step leading to ferroptosis. In the upstream of lipid peroxidation, the key enzymes responsible for membrane phospholipid synthesis are long-chain acyl-CoA synthase 4 (ACSL4) and lysolecithin acetyltransferase 3 (LPCAT3). ACSL4 catalyzes the combination of acetyl coenzyme A with arachidonic acid (AA) and adrenal acid in polyunsaturated fatty acids (PUFAs) to form long-chain polyunsaturated fatty acyl-coenzyme A. Subsequently, LPCAT3 combines this compound with lysophosphatidylethanolamine to form PUFA-containing phospholipid (PUFA-PL). Due to the presence of diallyl in PUFA-PL, which can easily undergo peroxidation, the peroxidation of PUFA-PLs occurs non-enzymatically via the Fenton reaction catalyzed by ferrous ions (8,9). Hydroxyl radicals serve as catalysts for the peroxidation of different biological macromolecules in cells, including PUFAs. The phospholipid bilayer has an important role in various cellular functions. Phospholipids consist of hydrophilic phosphoglycerol and hydrophobic PUFA chains. Peroxidation of these PUFA chains results in the disruption of the cellular phospholipid bilayer membrane structure, which increases membrane permeability and ultimately results in cell death (10,11).

The high level of expression of ACSL4 is considered to be a marker of ferroptosis. ACSL4 regulates ferroptosis through a signaling pathway. It may be more similar to caspase-3, the executor of apoptosis, than a housekeeping protein (12). Artemisinin (ART) and dihydroartemisinin (DHA) can affect this target (13).

Driving factors of ferroptosis: Iron metabolism

Iron has a key role in the development of ferroptosis. Unstable intracellular iron (Fe2+) can generate a substantial amount of reactive oxygen species (ROS) through the Fenton reaction, providing enough raw material for lipid peroxidation. Iron is also a cofactor of lipid peroxidase enzymes [AA lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase] and can determine their activity (2,3). Accumulation of excess iron may induce ferroptosis in individuals with cancer (1416). Transferrin (TF) receptor 1 (TFR1) in the membrane is responsible for transporting Fe3+ into cells and can be used as a biomarker for ferroptosis (17). Divalent metal transporter 1 (DMT1) facilitates the conversion of Fe3+ to Fe2+. Excess iron is stored within ferritin, which consists of two parts: Ferritin light chain and ferritin heavy chain 1 (FTH1) (18,19). Thus, the abundance of ferritin, particularly the presence of FTH1, plays a key role in suppressing ferroptosis (20). In addition, intracellular iron is predominantly sequestered within ferritin in an inert form. The autophagic breakdown of ferritin releases stored iron into the labile iron pool (LIP). Inhibiting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy decreases the level of the LIP; thus mitigating ferroptosis (21). In contrast, enhancing ferritinophagy by inhibiting cytosolic glutamate oxaloacetate transaminase 1 increases the LIP, thus facilitating ferroptosis. Furthermore, the redox state of iron plays an important role in ferroptosis: Fe2+ promotes ferroptosis, while Fe3+ remains inert and is stored within ferritin (22). The application of desferriamine or silencing of TFRs can reverse ferroptosis induced by erastin, a classical ferroptosis inducer. Studies have shown that ART compounds (ARTCs) and β-elemene also act on iron metabolism (2325).

Ferroptosis defense factor: The glutathione (GSH) peroxidase 4 (GPX4)-GSH system

GPX4 is an essential enzyme that catalyzes the breakdown of lipid peroxides. GPX4 acts as an important suppressor of ferroptosis. GPX4 relies on the cofactor GSH to convert harmful lipid peroxides into harmless lipid alcohols, resulting in the oxidation of glutathione into oxidized GSH (GSSG) (26). GSH synthesis requires cysteine as the reactant, which is transported into the cell by the Gys/Glu reverse transporter (xCT system) located outside the cell. The xCT system consists of the solute carrier family 7 member 11 (SLC7A11) and SLC3A2 subunits; SLC7A11 is overexpressed in ~70% of human tumor cells (3).

The SLC7A11-GSH-GPX4 pathway plays a key role in protecting against ferroptosis. However, certain cancer cell lines are resistant to ferroptosis even in the absence of functional GPX4, which indicates that alternative defense mechanisms against ferroptosis are in place (27). In addition, GPX4 is necessary for the proper functioning of various peripheral tissues, including kidney tubular cells and specific neuronal subgroups in mice (28). Thus, targeting GPX4 may lead to significant side effects unless therapeutic interventions can be used to precisely target tumor cells (29). Limiting the availability of cysteine/cysteine in cells by inhibiting the xCT system is a highly promising approach, particularly because knocking out the SLC7A11 gene in mice does not lead to any serious health problems (30). In addition, an inverse relationship was found between the level of expression of SLC3A2 and/or SLC7A11 and the clinical prognosis of individuals with melanoma and glioma. This observation reinforces the efficacy of targeting this pathway (31,32). Numerous natural products that can induce ferroptosis were found to affect this pathway. However, strong inhibition of GPX4 may be life-threatening (29).

Ferroptosis defense factor: The p62-Kelch-like ECH-associated protein 1 (KEAP1)-NF-E2-related factor 2 (NRF2) pathway and the adenosine-monophosphate-activated protein kinase (AMPK) pathway

Tumor drug resistance arises due to different mechanisms; among them, a significant contributor is the disturbance of the redox equilibrium. Tumor cells promote their resistance to oxidative stress by decreasing the production of ROS levels, imparting acquired drug resistance. The KEAP1-NRF2 pathway serves as a crucial antioxidant defense mechanism. A study found that this pathway negatively affects ferroptosis regulation (33).

The protective role of NRF2 differs based on the cellular and tissue environment. For instance, in pancreatic cancer cells, NRF2 hinders ferroptosis by stimulating microsomal glutathione S-transferase 1 (34), which in turn inhibits ALOX5. By contrast, in hepatocarcinoma cells, NRF2 promotes resistance to ferroptosis by controlling ferritin levels (35). In addition, PUFA biosynthesis can regulate sensitivity to ferroptosis and energy stress-induced activation of AMPK can limit the biosynthesis of PUFA by regulating acetyl-CoA carboxylase. Hence, AMPK can inhibit lipid peroxidation and ferroptosis (22). Numerous natural products promote ferroptosis by inhibiting the Keap1-Nrf2 pathway or the AMPK pathway.

Other ferroptosis defense factors

A study found that ferroptosis suppressor protein 1 (FSP1) plays a key role in protecting against ferroptosis (36). FSP1 is located on the plasma membrane and functions as an NAD(P)H-dependent oxidoreductase. It can convert ubiquinone (CoQH) to reduced ubiquinone (CoQH2) (37). Besides transferring electrons in the mitochondria, CoQH2 can capture lipid peroxidation free radicals; thus, inhibiting lipid peroxidation and ferroptosis. The FSP1-CoQH2 system protects cells from undergoing ferroptosis.

When GPX4 is deactivated, the flow through dihydroorotate dehydrogenase (DHODH) increases substantially, leading to an increase in the production of CoQH2. This increase in CoQH2 counteracts lipid peroxidation and protects against ferroptosis in the mitochondria (38). Therefore, the DHODH-CoQH2 system can be considered to act as a second defense system against ferroptosis.

A study reported that GTP cyclohydrolase 1 suppresses ferroptosis by producing BH4 as a radical-trapping antioxidant, as well as via GCH1-mediated production of CoQH2 and phospholipids containing two PUFA tails (39). Therefore, the GCH1-BH4 system is another ferroptosis defense system.

Most studies on the induction of ferroptosis by natural products have focused on the driving factors of ferroptosis, the SLC7A11-GSH-GPX4 pathway and the p62-Keap1-Nrf2 pathway. Only a few studies have investigated other pathways, such as the PI3K-AKT mTOR pathway and the Hippo signaling pathway. A study found that overactive mutations related to PI3K-AKT-mTOR signaling can induce cancer cells and protect them from oxidative stress and ferroptosis through sterol receptor element binding protein-1/stearoyl-CoA desaturase 1-mediated adipogenesis (40). Another study found that the Hippo pathway and ferroptosis share upstream regulatory factors in mechanical transduction and matrix hardness, such as piezo type mechanosensitive ion channel component 1, integrin and transient receptor potential vanilloid 1. Therefore, mechanical signal transduction can affect the disease by serving as an upstream regulatory factor for the Hippo pathway and ferroptosis (41).

Natural ferroptosis inducers are compounds isolated and extracted from animals or plants that have the ability to induce ferroptosis. These include monomeric compounds extracted from Traditional Chinese Medicine, such as artesunate. Synthetic ferroptosis inducers refer to artificially synthesized compounds, such as erastin. Several studies have found that natural substances such as ARTs, tanshinones, isothiocyanate (ITC) and gallic acid, among others, can trigger ferroptosis (42). These natural products act on different targets of the ferroptosis removal pathway, inducing ferroptosis in tumor cells or synergistically increasing the anti-tumor effects of numerous drugs through the ferroptosis pathway.

In the present review, studies were systematically collected and categorized in relation to the role of natural products in inducing ferroptosis for cancer therapy. Their chemical structures are presented in Fig. 2. The study focused on describing their effects and mechanisms. To better understand the natural products that induce ferroptosis, the stimulating and inhibitory factors of ferroptosis were summarized and the key pathways and targets involved were described. After classifying the natural products, the roles of natural ferroptosis inducers in cancer treatment were discussed from various aspects, including their effects and mechanisms, synergistic effects and structural improvements. This review may act as a framework for future studies. The mechanism of drug action, synergistic effects and structural improvements are summarized in Table I.

Table I.

Phytochemicals in the treatment of cancer acting by activating ferroptosis.

Table I.

Phytochemicals in the treatment of cancer acting by activating ferroptosis.

Compound nameCell linesMechanismSynergy, reversal and increased sensitivityChemical modification and drug delivery systems(Refs.)
ArtesunateHuman MM cell lines↑Ferroptosis--(13)
MM1S/RPMI8226↓GPX4
↑LPO
↑ACSL4
ArtesunateBurkitt's lymphoma↑Ferroptosis--(43)
cell lines DAUDI and↑ATF4-CHOP-
CA-46pathway
ArtesunateHuman pancreatic↑Ferroptosis--(44)
cancer cell lines↑mRNA and
PaTU8988 and AsPC1protein levels of GRP78
ArtesunateHepatocellular↑FerroptosisCombined treatment-(45)
carcinoma cell lines↑LPOwith ARTCs and
Huh7, SNU-449 and↑MDAsorafenib
SNU-182↑ROS
↓GSH
ArtesunateHead and neck cancer↑FerroptosisInhibition of Nrf2-(46)
cell line HN2-10↑ROScombined with
(cisplatin-resistant)↓GSHartesunate
ArtesunateProstate cancer↑Ferroptosis,Artesunate inhibits-(47)
cell lines DU145, PC3↑ROSthe growth of
and LNCaP↓Cell cycle docetaxel-resistant
(docetaxel-resistant)activatingprostate cancer cells
proteins
ArtesunateHuman cervical↑Ferroptosis- Phosphorescentrhenium(I)(48)
cancer HeLa↓GSH complexes conjugated
↓GPX4 with artesunate
↑LPO
ArtesunateMouse breast cancer↑Ferroptosis-Transferrin-(49)
cell line 4T1↓GPX4 targeted
↑ROS cascade
↑ACSL4 nanoplatform
↓xCT
ArtesunateHNE-1 cells↑Ferroptosis-The complex carries(50)
↓GPX4 (AST/AAPAMAM@HA)
↑ROS
↑LPO
DihydroartemisininHuman tumor cell lines↑Ferroptosis
NCI-H292, HCT116,↓GPX4--(24)
HT29, SW480,↑ROS
MDA-MB-453 and
MCF-7
DihydroartemisininMouse lung cancer↑Ferroptosis- Dihydroartemisinin(51)
cell lines Lewis cells↓GPX4 combined with Ce6
↑ROS
DihydroartemisininGlioblastoma cell lines↑Ferroptosis--(52)
U87, A172↓GPX4
↑ROS
↑ACSL4
↓xCT
↑LPO
DihydroartemisininHepatocellular↑FerroptosisCombined treatment-(53)
carcinoma cell line↓GPX4with
↓ROS Dihydroartemisinin
↑ACSL4and sorafenib
↓xCT
DihydroartemisininHuman leukemia↑Ferroptosis Dihydroartemisinin-(54)
cell line K562↓GPX4inhibits the growth of
↓GSH docetaxel-resistant
↓FTHleukemia cells
↑ROS
DihydroartemisininLeukemic cell lines↑Ferroptosis--(55)
↑FTH1
DihydroartemisininPancreatic ductal↑Ferroptosis-A Dihydroartemisinin-(56)
adenocarcinoma↓GPX4 conjugated amphiphilic
Panc02 cell line↑ACSL4 copolymer is synthesized
↑xCT
DihydroartemisininHuman cervical cancer↑Ferroptosis--(57)
cell lines HeLa and↓GPX4
SiHa↓GSH
↑ROS
↑LPO
DihydroartemisininHuman lung↑Ferroptosis Dihydroartemisinin-(58)
adenocarcinoma cell↓GPX4enhances gefitinib
lines A549, HCC827↓GSHcytotoxicity through
and H1975↑ROSferroptosis
DihydroartemisininBreast cell lines and↑Ferroptosis-Chemo- and(59)
patient-derived↓GPX4 stereoselective synthesis
pancreatic cancer cells↑ROS of a complex small
↓xCT molecule chimeras of
salinomycin derivatives
and the iron-reactive
dihydroartemisinin
DihydroartemisininHeLa, A549, HepG2↑Ferroptosis-Synthesis of(60)
and 4T1 cells↓GPX4 Tf-DHA-MnO 2;
↓GSH Tf-DHA-ASO-MnO2 and
↑ROS FAM-Tf-DHA-ASOMnO2
DihydroartemisininHuman laryngeal↑Ferroptosis- (61)
carcinoma HEP-2;↓GPX4
nasopharyngeal↑ROS
carcinoma cell
lines 5–8F, CNE-1,
CNE-2 and CNE-2Z
DihydroartemisininHuman acute↑Ferroptosis--(62)
promyelocytic leukemia↓GPX4
cell line HL60; acute↓GSH
myeloid leukemia↑ROS
cell line KG1; acute
monocytic leukemia cell
line THP-1
DihydroartemisininPancreatic cancer cell↑FerroptosisCombined with DHA-(63)
lines PANC1 and↓GPX4and cisplatin
SW1990↑ROS
↓xCT
DihydroartemisininMouse lung cancer cells↑Ferroptosis-A nanoreactor boosts(64)
line Lewis cells↓GPX4 chemodynamic therapy
↑ROS and ferroptosis
↑LPO
DihydroartemisininMurine colon↑Ferroptosis-Co-delivery of(65)
adenocarcinoma CT26↓GPX4 dihydroartemisinin and
and MC38 cells↑ROS pyropheophorbide-iron
Dihydroisotanshinone IHuman breast cancer↑Ferroptosis--(66)
cell lines MCF-7 and↓GPX4
MDA-MB-231
Dihydrotanshinone IHuman glioma cell lines↑Ferroptosis--(67)
U251 and U87↓GPX4
↑ACSL4
Tanshinone IIAGastric cancer cell lines↑Ferroptosis
BGC-823 and NCI-H87↓GPX4
↑ROS
↑LPO
↓xCT--(68)
Tanshinone IIAHuman gastric cancer↑Ferroptosis--(69)
cell lines SGC-7901 and↑LPO
BGC-823; normal human↓GSH
gastric epithelial cell line
GES-1
CryptotanshinoneNon-small cell lung↑Ferroptosis--(70)
cancer cell lines A549↑ROS
and NCI-H520↑LPO
↓GPX4
DihydroisotanshinoneHuman lung↑Ferroptosis--(71)
adenocarcinoma cell line↓GPX4
A549; human lung large↑ROS
cell carcinoma cell line
H460; human normal
lung fibroblast cell line
IMR-90
SulforaphaneHuman AML cell lines↑Ferroptosis--(72)
U-937 and MV4-11↓GPX4
↓GSH
Phenethyl isothiocyanateMurine osteosarcoma↓GSH--(73)
cell line K7M2↑ROS
SulforaphaneHuman SCLC cell lines↑Ferroptosis--(74)
NCI-H69, NCI-H82 and↓xCT
NCI-H69AR
phenethyl isothiocyanateHuman pancreatic↑FerroptosisCombined with-(75)
cancer cell lines↑ROScotylenin A and
MIAPaCa-2, PANC-1 and phenethyl
CFPAC-1 isothiocyanate
IsothiocyanateHuman prostate cancer↑Ferroptosis- Isothiocyanate-containing(76)
cell line PCa↑LPO hybrid androgen receptor
↓GSH antagonist
Gallic acidHuman cervical cancer↑Ferroptosis--(77)
HeLa;↑LPO
neuroblastoma cell line
SH-SY5Y
Gallic acidBreast cancer cell line↑Ferroptosis--(78)
MDA-MB-231;↑ROS
melanoma cancer cell
line and human dermal
fibroblast cell line
PiperlongumineHuman pancreatic cancer↑Ferroptosis--(79)
cell lines MIAPaCa-2,↑ROS
PANC-1, CFPAC-1 and
BxPC-3
Saponin Albiziabioside AHuman breast cancer cell↑Ferroptosis--(80)
line MCF-7↓GPX4
ErianinHuman lung cancer cell↑Ferroptosis--(81)
lines H460 and H-1299↓GPX4
↓GSH
↑ROS
ErianinHuman lung cancer cell↑Ferroptosis--(82)
lines H460 and H1299↑ROS
↑LPO
↓GSH
β-ElemeneHuman non-small lung↑Ferroptosisβ-Elemene enhances (83)
cancer cell lines H1975,↓FTH1erlotinib sensitivity
H1650 and H1819↓ Nrf2through induction of
↑ROSferroptosis
↑LPO
↓GSH
↓GPX4
β-ElemeneHuman colon cancer cell↑FerroptosisCombined with-(23)
lines HCT116, Lovo and↓FTH1β-elemene and
CaCO2↑ROScetuximab
↓GPX4
↓xCT
IsoliquiritinBreast cancer cell lines↑Ferroptosis--(84)
DA-MB-231 and MCF-7↓GPX4
↓xCT
QuercetinBreast cancer cell line↑Ferroptosis--(85)
MCF-7↓FTH1
QuercetinHuman hepatocellular↑Ferroptosis--(86)
carcinoma cell line↑LPO
HepG2↑ROS

[i] ACSL4, acyl-coenzyme A synthetase long chain family member 4; GPX4, GSH peroxidase 4; GSH, glutathione; SLC7A11, solute carrier family 7 member 11, also known as xCT; ATF4, activating transcription factor 4; CHOP,C/EBP homologous protein; GRP78, glucose-regulated protein 78; MDA, malonaldehyde; LPO, lipid peroxidation; ROS, reactive oxygen species; FTH, ferritin heavy chain.

ARTCs

ART is obtained from the Chinese herb Artemisia annua (Asteraceae) and was initially used for its promising effects against malaria. Later, researchers found that ART derivatives not only have anti-malarial properties but also anti-cancer effects (87). ARTCs are sesquiterpene lactones and include ART, artemether, arteether, artesunate (ATS) and DHA. ATS and DHA are widely used in anti-tumor research because they are highly soluble in water. They contain peroxides that are essential for maintaining the activity of ARTCs. The common structure of a peroxide-internal bridge is essential for the anti-tumor effects of ARTCs (88,89) ARTCs can cause cell cycle arrest of tumor cells (90), inhibit angiogenesis (91), inhibit cell metastasis and invasion (92), cause DNA damage (93) and induce apoptosis and ferroptosis (25,94).

ARTC-induced ferroptosis in cancer treatment

In 2001, Efferth et al (95) found that ATS has anti-cancer effects. They analyzed the anticancer activity of ARTCs against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ARTCs were most effective against leukemia and colon cancer cell lines; they also showed intermediate effectiveness in controlling melanomas and breast, ovarian, prostate, central nervous system and renal cancer cell lines. By contrast, non-small cell lung cancer (NSCLC) cell lines showed low sensitivity to ARTCs (95). Other studies later found that Fe2+ can enhance the anti-tumor effect of ART derivatives and that desferriamine can reverse this effect (9698). At that time, researchers hypothesized that intracellular Fe2+ reacted with the peroxy bridge structure in DHA and generated carbon-centered free radicals, thus inhibiting cell proliferation (99).

In 2012, a novel form of iron-dependent cell death termed ferroptosis was described and ARTCs were found to be closely associated with the characteristics of ferroptosis (100). Research on the treatment of cancer by ARTCs through ferroptosis was performed by several groups. The discovery of ferroptosis also partially explained the mechanism underlying the inhibitory effects of ARTCs on tumor growth. ATS and DHA are often used as ferroptosis inducers to study glioma, ovarian cancer, leukemia, pancreatic cancer, neuroma and gastrointestinal tumors in vivo and in vitro. Methods such as the MTT, Cell Counting Kit-8 and lactate dehydrogenase (LDH) assays are used to detect cell death. The levels of iron, GSH and malondialdehyde (MDA) are determined. Ferritin, ferritin heavy chain, nuclear activator 4, FTH1 SLC3A2, heme oxygenase, GPX4, TFR and ferroportin 1 (FPN1) are also detected (44,101103).

ATS is a clinically versatile ARTC used for treating mild-to-severe malaria infection (104). Therefore, it is a promising compound for application in anti-tumor clinical treatment. Several clinical studies have investigated ATS, mainly focusing on colorectal cancer and metastatic breast cancer. Among the five projects that were initiated, three have been completed (105). Compared to ATS, DHA can be further improved due to its structural characteristics, such as poor water solubility, instability and rapid clearance (106).

Mechanisms of ARTC-induced ferroptosis

The dysregulation of iron metabolism contributes significantly to ferroptosis. Tumor cells usually have higher iron levels compared to normal cells, which highlights the significance of targeting iron metabolism for treating and preventing tumors (107,108). Studies have shown that the primary mechanism underlying the ferroptosis-inducing effect of ARTCs is the enhancement of ferritin degradation by lysosomes. This increases the level of free iron, which can ultimately induce ferroptosis by activating the Fenton reaction and peroxides (24,25). Both deferoxamine and ferrostatin-1 can inhibit ferroptosis by decreasing free iron levels through their iron-scavenging properties (61,109). ARTCs can counteract the effects of these compounds, indicating that ARTCs can trigger ferroptosis by affecting iron metabolism (108). Certain studies have shown that administering ARTCs stimulates lysosomal activity and facilitates the degradation of ferritin, which can increase lysosomal iron levels; thus, ARTCs can impart cytotoxic effects on cancer cells (100,110). Chen et al (24) found that DHA and erastin can induce ferroptosis by regulating iron metabolism, but the increase in lysosomal degradation of ferritin and dysregulation of iron in cells induced by DHA is not related to autophagy. A study also found that ARTCs showed negligible toxic effects on cells in which NCOA4 was knocked down (110). NCOA4 is a cargo receptor that mediates the delivery and degradation of ferritin in lysosomes (18,111,112). Studies have found that DHA induces autophagy, thus initiating ferroptosis. For instance, DHA-induced autophagy, through the activation of the AMPK/mTOR/p70S6 k pathway, can increase the size of the LIP and promote lipid peroxidation, ultimately resulting in ferroptosis (62). In addition, ARTCs can also induce ferroptosis by reducing the level of expression of GPX4. DHA can significantly reduce the expression of GPX4, leading to ferroptosis (51), but it does not affect the level of expression of ACSL4 and xCT (52). DHA and sorafenib share a similar mechanism and can decrease the levels of GPX4 and GSH (53). In multidrug-resistant leukemia cells, DHA decreases the viability of multi-drug resistant K562 cells and enhances their sensitivity to adriamycin ADM by promoting ferroptosis induced by the downregulation of GSH levels and the expression of GPX4, iron regulatory protein 2 and FTH (54). However, GSH levels may fall and the expression of GPX4 may decrease due to the secondary effects of the Fenton reaction induced by iron ions after ARTCs cause an imbalance in iron metabolism. ARTCs contain an endoperoxide structure. The internal peroxide structure of these compounds can react with Fe2+ ions to produce ROS, thus damaging cells (22,113115). Before ferroptosis was discovered, researchers speculated that this may be the reason underlying the inhibitory effects of ARTCs on tumors. However, the relationship between ART-induced ferroptosis and its ability to stimulate ROS production has remained to be demonstrated. The initial stage in ART-induced ferroptosis may involve the production of ROS by ARTCs and Fe2+. A study found that DHA-induced ferroptosis in acute myeloid leukemia is associated with iron metabolism and metallothionein (55).

Endoplasmic reticulum stress may be the link between ferroptosis and apoptosis (116). ATS can induce ferroptosis in various types of Burkitt's lymphoma cells and cause a significant ERS response in tumor cells. Activating the activating transcription factor 4-C/EBP homologous protein-glutamylcyclotransferase 1 (CHAC1) pathway upregulates the expression of CHAC1 and degrades intracellular GSH, thereby reducing the ability of lymphoma cells to resist ferroptosis (43). However, recent reviews have not commented on the relationship between endoplasmic reticulum stress and ferroptosis (22,29,39). As the endoplasmic reticulum is the site of ferroptosis, endoplasmic reticulum stress may be a secondary effect of ferroptosis. However, this hypothesis remains to be confirmed.

Certain studies have shown that ARTCs can disrupt the equilibrium of intracellular iron metabolism by facilitating the degradation of ferritin via lysosomes and autophagy. This process leads to the release of ferrous ions, a notable increase in ROS levels and an accumulation of lipid peroxides. This disruption promotes ferroptosis, along with a decrease in the level of expression of GPX4 and depletion of GSH. ARTCs can not only induce ferroptosis but also induce apoptosis and damage DNA. These mechanisms and their relationships need to be further investigated, particularly the relationship between ROS production and various mechanisms. In addition, the administration of ARTCs leads to alterations in several proteins involved in the regulation of iron metabolism. These proteins, including lactoferrin, TFR1 and TFR2, TF transporter protein and ceruloplasmin, can serve as tumor markers (117). ARTCs acting on targets of ferroptosis are shown in Fig. 3.

Combination of ARTCs by inducing ferroptosis in cancer treatment

The challenges of severe side effects and acquired drug resistance in tumor cells have hindered clinical treatment. Hence, treatment strategies that are more effective and less toxic need to be developed. Several studies have investigated the synergistic effects of ARTCs and the reversal of drug resistance. Synergistic studies combine first-line clinical antitumor drugs with ARTCs, which often serve as adjuvants. This method can be further studied as a cancer treatment strategy.

Although sorafenib is used as a first-line targeted treatment drug for liver cancer, it faces problems related to drug resistance. The activation of lysosomes by ATS, combined with the pro-oxidative effects of sorafenib, synergistically promotes several sequential reactions. These reactions involve the activation of lysosomal cathepsin B/L, degradation of ferritin, lipid peroxidation, and finally, induction of ferroptosis. Hence, ATS can also be used to enhance the sensitivity of sorafenib in the treatment of hepatocellular carcinoma (HCC) (84). In another study, the simultaneous administration of DHA and Sora synergistically inhibited HepG2 and SW480 cells. This combination induced ferroptosis by increasing the levels of lipid ROS, LIP and MDA, while simultaneously decreasing the level of GSH in HepG2 cells (53). Following the combined administration of DHA and DDP, the experimental results showed that they synergistically inhibited the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and induced DNA damage. A further study found that ferroptosis contributed to the cytotoxic effects on PDAC cells after DHA and DDP were administered simultaneously. The treatment also led to the accumulation of large amounts of free iron and unrestricted lipid peroxidation (63). The study found that DHA and cisplatin can induce DNA damage and iron-dependent cell death, both of which can inhibit tumor cell proliferation. However, which mechanism plays a more significant role in the suppression of tumor growth remains elusive, and thus, further studies are needed to address this question.

Certain studies have used DHA in combination with doxorubicin, RSL3 and erastin, respectively, and found that ARTCs can have a sensitization role by regulating iron metabolism and inducing ferroptosis (24). The inhibition of some related pathways or proteins may also affect ferroptosis. For instance, a study suggested that combining ATS application with glucose-regulated protein 78 inhibition may be a novel technique for effectively killing KRAS mutant PDAC cells (44). A study found that ATF3 may sensitize gastric cancer (GC) cells to cisplatin by inducing ferroptosis via the inhibition of Nrf2/Keap1/xCT signaling (46). Another study reported that activation of the p62-Keap1-NRF2 pathway can protect HCC cells against ferroptosis (35). Ferroptosis involves oxidation reactions. As a protective factor against oxidation and reduction, Keap1-NRF2 is an important target for ferroptosis. Inhibition of NRF2 can reverse drug resistance. ATS can trigger the activation of the Nrf2-antioxidant response element pathway in head and neck cancer (HNC) cells, imparting resistance against ferroptosis. Silencing Keap1, a negative regulator of Nrf2, reduced the sensitivity of HNC cells to ATS. Genetic silencing of Nrf2 or treatment with trigonelline was found to reverse the ferroptosis resistance observed in Keap1-silenced and cisplatin-resistant HNC cells to ATS in vitro and in vivo (46). Another study found that ARTCs strongly inhibited the growth and proliferation of docetaxel-resistant prostate carcinoma (PCa) cells through mechanisms involving ferroptosis and apoptosis, whereas normal cells remained unaffected (47). The increase in oxidative damage and the impairment of antioxidant defense mechanisms strongly influence DHA-induced ferroptosis, thus contributing to the sensitivity of multidrug-resistant leukemia cells to DHA (54). The activation of the apoptosis cascade is the primary mechanism for eliminating cancer cells. However, in numerous types of cancer cell, the apoptotic pathway is frequently obstructed, leading to the development of strong resistance to drugs (118). Ferroptosis induction may reverse this condition.

Overall, the induction of ferroptosis by ARTCs can specifically inhibit tumor cells and exhibit multi-target activity. Thus, ARTCs are promising agents for administering combination therapy and reversing drug resistance. However, further studies are needed to confirm these speculations. of notes, in certain studies on the reversal of drug resistance by ATS, the occurrence of ferroptosis was not reported. For instance, the sensitization effect of ATS mainly depends on cell cycle arrest and mitochondrial dysfunction in bladder cancer (119). In addition, inhibition of the Nrf2-ARE pathway may be an important way for ARTCs to reverse drug resistance (46).

Drug delivery systems and chemical modification of ARTCs

Delivery systems and modifications of the structures of compounds are important in improving the pharmacological activity of compounds. As DHA has poor water solubility and a short half-life in vivo, most improvements in ARTCs are mainly related to DHA. Improvements in drug formulations involving DHA have enhanced its efficacy. Researchers have developed advanced techniques, such as polymeric nanoparticles, liposomes and metal-organic frameworks to optimize the therapeutic potential of DHA; these techniques can be used as a single-drug treatment strategy or as a part of multidrug therapy (120).

Iron plays an important role in ARTC-induced ferroptosis in cancer cells. Although certain researchers argue that not all methods of adding iron can promote ferroptosis induced by ARTCs, as iron can act as a cofactor for enzymes involved in cellular proliferation and unwanted negative effects cannot be excluded, which may promote tumor growth rather than inhibiting it (121,122). However, adding iron to the nanoreactor of DHA can strongly promote ferroptosis. Using chemodynamic therapy as an example, which relies on intracellular iron ions and H2O2, certain researchers developed and characterized the DHA@ iron-based metal-organic framework (MIL-101) nanoreactor. This nanoreactor degraded in the acidic tumor microenvironment, releasing DHA and iron ions. In subsequent experiments, DHA@MIL-101 significantly increased intracellular iron ions due to the disintegration of the nanoreactor and the recruitment of DHA, eventually triggering ROS production. Simultaneously, ROS production induced ferroptosis by depleting GSH, inactivating GPX4 and leading to the accumulation of lipid peroxide (64). Another study found that DHA can induce ferroptosis in an immunogenic manner. Furthermore, the in vivo antitumor efficacy of DHA was maximized by co-delivering a cholesterol derivative of DHA and pyropheophorbide-iron (PyroFe) in Zn-pyrophosphate @DHA/Pyro-Fe core-shell nanoparticles (65).

The use of compounds with similar effects but different mechanisms by synthesizing chimeric compounds is also a promising strategy that may be assessed for cancer treatment. Salinomycin can eliminate cancer cells in the mesenchymal state by sequestering iron within lysosomes, capitalizing on the iron dependence of this cell state. In a study, a series of structurally complex small-molecule chimers combining salinomycin derivatives and iron-reactive DHA were synthesized with chemoselectivity and stereoselectivity. These chimers accumulated in lysosomes and interacted with iron to release bioactive species. As a result, they induced ferroptosis in drug-tolerant pancreatic cancer cells and biopsy-derived organoids of PDAC (59). In a study, two ATS-conjugated phosphorescent rhenium (I) complexes were synthesized and the complexes exhibited high cytotoxicity against cancer cell lines. They also induced apoptosis and ferroptosis in HeLa cells (48).

A multifunctional nanodrug (Tf-DHA-ASO-MnO2) was engineered using manganese dioxide nanosheets, which was triple-dressed with TF, DHA and antisense oligonucleotide sequences. This nanodrug exhibited potent targeted therapeutic effects on cancer by inducing ferroptosis. This effect was achieved through the combined actions of glutathione depletion, ROS generation and the downregulation of glutathione peroxidase 4, which resulted in excessive production of lipid peroxides (60). Some researchers used pH-sensitive acetylated β-cyclodextrin to effectively deliver DHA for combined tumor ferroptosis therapy and chemodynamic therapy, based on their synergistic effects (123). Although photodynamic therapy (PDT) is noninvasive, low in toxicity and selectively targeted, it may be ineffective against malignant cells. However, in a study, combined treatment with DHA and Ce6 yielded very high efficacy in controlling lung cancer. The study showed that the downregulation of GPX4 via DHA-induced ferroptosis significantly increased the effectiveness of PDT (51). In addition, studies have found that the reaction of endoperoxide compounds with iron can also trigger ferroptosis (22,113). The fourth class of the ferroptosis-inducing compound FINO2 was discovered by the Woerpel group in 2016 through the synthesis and analysis of a series of 1,2-dioxolane-containing compounds (113). FINO2 and ARTCs have similar characteristics of inducing ferroptosis. In a study, the researchers used a TF-targeted cascading nanoplatform Tf-PEG-modified mesoporous polydopamine (MPDA)@artesunate/ML385 (AM) based on mesoporous polydopamine, co-encapsulating the ferroptosis-inducing agent ART and the Nrf2-specific inhibitor ML385. This increased intracellular ROS levels, consequently enhancing ferroptosis (49). In another study, the investigators developed programmable carriers for ART that respond to enzymes and ROS, adjusting their size and charge to increase stability and overcome challenges associated with solid tumors. Through the electrostatic interaction between dendrimer-ART/AA-polyamidoamine (PAMAM) and hyaluronic acid (HA), these carriers (ART/AA-PAMAM@HA) were formed. They enabled deep tumor penetration and selective drug release. Anti-tumor efficacy assessed in vivo showed a tumor inhibition ratio of 46.92%. The study described a novel anti-tumor approach that can induce ferroptosis by modulating redox homeostasis (50). In another study, DHA-conjugated amphiphilic copolymers were synthesized and intracellular acidity and oxidation dual-responsive DHA nanoparticles were engineered for the targeted co-delivery of DHA and RAS-selective lethal (RSL-3) to tumors. DHA-conjugated and RSL-3-loaded nanoparticles (PDBA@RSL-3) effectively induced ferroptosis of tumor cells in a xenograft mouse model bearing Panc02 tumors (56). Several studies have investigated the application of nanomaterials in the induction of ferroptosis by ARTCs (124128).

To summarize, the chimers involved in ARTCs and new drug delivery systems involving iron may be important development directions in the future. Delivery systems can increase the targeting and solubility of drugs. Studies on synergistic reactions and reversal of drug resistance can serve as its research foundation. In addition, enhancing water solubility can also improve drug efficacy.

Tanshinone derivatives (Tans)

The tanshinone extract from Salvia miltiorrhiza Bge. contains >90 different bioactive monomers. Among them, tanshinone I (Tan I), tanshinone IIA (Tan IIA), dihydrotanshinone I (DHTI), dihydroisotanshinone I (DT) and cryptotanshinone (CPT) have high activity levels (129,130). The above-mentioned tanshinone compounds are called Tans. Tanshinone generally has four rings: Naphthalene or tetrahydronaphthalene rings A and B, a normal or paraquinone or lactone ring C and a furan or dihydrofuran ring D (Fig. 2). While the molecular framework of the four primary constituents of tanshinone is similar, variations exist in the groups, their positions and the positions of double bonds (131,132). Several studies have shown that tanshinone and its derivatives can inhibit acetylcholinesterase and has antibacterial, anti-inflammatory and anti-tumor effects (133,134). The antitumor activities of tanshinones include the induction of apoptosis and autophagy, modulation of the cell cycle, and inhibition of proliferation, invasion, metastasis and angiogenesis (131,135139). Tanshinones can also inhibit tumor growth by inducing ferroptosis (66,71).

Tans-induced ferroptosis in cancer treatment

In 1991, Wu et al (140) identified 15 tanshinone analogs isolated from the chloroform extract of Danshen roots (Salvia miltiorrhiza Radix) and assessed their cytotoxic effects against the KB, Hela, Colo-205 and Hep-2 carcinoma cell lines. Some of these analogs were found to be highly effective against tumor cells. Their findings indicated that the flat phenanthrene ring in tanshinone may strongly influence its ability to bind DNA molecules, whereas the furanoquinone component may generate reactive free radicals close to the DNA base, thus damaging the DNA (140). Later, multiple studies were conducted on tanshinone.

Tanshinone compounds can inhibit various tumor types, including breast cancer, GC, acute myeloid leukemia, lung cancer, osteosarcoma, liver cancer, glioma and oral squamous cell carcinoma (141148). In 2019, a study showed that DT can arrest the proliferation of breast cancer cells, including MCF-7 and MDA-MB-231 cells. The researchers also found that DT triggered apoptosis and ferroptosis in these breast cancer cells, simultaneously suppressing the expression of the GPX4 protein (66). Wu et al (71) found that DT can induce ferroptosis and apoptosis in lung cancer cells. Several studies have also found that Tan IIA can induce ferroptosis in GC cells and inhibit the stemness of GC cells (68,69). Another study found that DHTI can inhibit the proliferation of human glioma cells, including U251 and U87 cells, by activating ferroptosis (67). In addition, CPT can induce ferroptosis in lung cancer cells, including the A549 and NCI-H520 NSCLC cell lines. Another study found that only 20% of cell death in cryptotanshinone is caused by caspase, while others may be caused by ferroptosis (70).

In a study, after ferroptosis was induced by tanshinone compounds in tumor cells, a series of substances related to ferroptosis were altered, including SLC7A11, ACSL-4, ROS, ferroportin, GPX4 and the GSH/GSSG ratio. These results suggested that tanshinone-induced ferroptosis may be related to these substances.

Mechanisms underlying Tans-induced ferroptosis

The primary mechanism that prevents cells from undergoing ferroptosis is the SLC7A11-GSH-GPX4 pathway. Studies have shown that Tan IIA can trigger ferroptosis by preventing the decrease in SLC7A11 levels, a process mediated by p53, in BGC-823 and NCI-H87 GC cells (68). P53 can be recruited to the SLC7A11 promoter region to block the transcription of SLC7A11 and induce ROS-mediated ferroptosis via a decrease in GSH production caused by the downregulation of xCT (149). In addition, Tan IIA can increase lipid peroxidation and upregulate the level of expression of prostaglandin-endoperoxide synthase 2 and CHAC1. Another study on GC found that Tan IIA can inhibit GC stem cells through SLC7A11-dependent ferroptosis (69). These results suggested that SLC7A11 may be an important target for Tan IIA-induced ferroptosis. However, a study showed that DT can inhibit the expression of GPX4 and subsequently induce ferroptosis through lipid peroxidation in vitro and in vivo (71). Of note, some researchers reported that DHTI can not only reduce the expression of GPX4 but also enhance the expression of ACSL-4, thus inducing ferroptosis in human U251 and U87 glioma cells (67). ACSL4 has a key role in fatty acid metabolism. It also activates long-chain unsaturated fatty acids, thus facilitating their involvement in the synthesis of membrane phospholipids and initiation of cell ferroptosis (150). Ferroptosis is associated with tumor growth inhibition and is a promising strategy for treating tumors. ACSL4 may be used as a biomarker for predicting the susceptibility of cells to ferroptosis (151). DHTI can also increase the levels of LDH and MDA in human glioma cells and decrease the GSH/GSSG ratio. A study showed that a high level of expression of the ferroptosis gene FTH1 in head and neck squamous cell carcinoma (HNSCC), and Tan IIA considerably inhibited HNSCC, partly through the suppression of FTH1 (152). Another study found that tanshinone functions as a coenzyme for NAD(P)H:quinone oxidoreductase 1 (NQO1), which detoxifies lipid peroxyl radicals and inhibits ferroptosis in vitro and in vivo. The researchers found a gain of function of NQO1 induced by tanshinone, which is a novel mechanism for inhibiting ferroptosis (153).

To summarize, some studies have reported that SLC7A11 inhibition may strongly influence ferroptosis induced by tanshinone compounds. In addition, GPX4 inhibition, which upregulates the expression of ACSL4, may also contribute to ferroptosis. The induction of NQO1 by tanshinone also needs to be further investigated. Researchers have reported that the molecular actions of tanshinone compounds primarily focus on apoptosis and cell-cycle modulation, which may represent only a part of their effects. Thus, further studies are needed to determine whether they interact with other proteins (154). Tans acting on targets of ferroptosis are presented in Fig. 3.

Drug combination of Tans in cancer therapy

Studies on the combination of tanshinone compounds with other drugs to induce ferroptosis are limited. However, several studies have investigated the synergistic effects and reversal of drug resistance of combination therapy. For instance, in studies on breast cancer, CPT and monomethylarsonous acid were found to promote the apoptosis of MCF-7 breast cancer cells (155). In addition, the combination of Tan IIA and paclitaxel can increase the sensitivity to chemotherapy (156), while the combination of Tan IIA and doxorubicin can enhance anti-tumor effects, reverse drug resistance and reduce adverse reactions (157,158). The effects of combination therapy primarily include increasing the levels of Bax, Bak and Caspase-9, decreasing the migration of β-catenin to the nucleus, reducing the activity of microtubule-associated proteins and impeding the phosphatase and tensin homolog/Akt pathway. CPT and DHT are highly efficacious in reversing P-glycoprotein-mediated multidrug resistance in colon cancer cells (159). Tanshinones can also increase the sensitivity of apoptosis-resistant colon cancer cells through autophagic cell death and p53-independent cytotoxicity (160).

To summarize, although numerous studies have used tanshinones for combination therapy, none have reported whether the combination therapy can induce ferroptosis to treat cancer. Thus, further research is needed to determine whether the combination of tanshinone compounds and other anti-tumor drugs can induce ferroptosis.

Chemical modification and drug delivery systems of Tans

Acetyltanshinone IIA (ATA) is a derivative of Tan IIA and is highly soluble in water. It has high pro-apoptotic effects on different cancer cell lines. Administering ATA stimulates Bax relocation, cytochrome c discharge, caspase-3 activation and apoptosis; it also arrests the growth of xenografted tumors (161). ATA triggers oxidation and endoplasmic reticulum stress and activates the expression of AMPK (162). These characteristics may be related to ferroptosis, but further research is necessary to confirm this relationship. TA12 is another derivative of Tan IIA, which can also activate ROS production and damage DNA, leading to cell-cycle arrest in the S phase (163).

Nanotechnology has received significant attention in recent years, as it can effectively overcome the gastrointestinal barrier. A study showed that poly-N-(2-hydroxypropyl) methacrylamide-coated wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles, carrying both CPT and silibinin, were more toxic to 4T1 cells and prevented their migration and invasion more effectively compared to the corresponding effects found in the cells treated with CPT alone (164).

To summarize, modified tanshinone compounds can increase anti-tumor effects by significantly increasing ROS and triggering oxidation. However, the relationship between these compounds and ferroptosis remains largely elusive and further study is required.

ITC derivatives

Cruciferous vegetables contain ~100 ITCs, which can have significant roles in fighting cancer (165). ITCs have a sulfur-containing functional group with N=C=S bonds (166). The commonly used ITC-containing compounds include phenethyl ITC (PEITC) from gluconasturtin in watercress and wasabi, and sulforaphane (SFN) from glucoraphanin in broccoli, cauliflower, brassicas and kale (167). Studies have suggested that phenylethyl ITC and sulforaphane have strong anticancer properties and exert their effects through the ferroptosis pathway (72,168).

ITC-induced ferroptosis in cancer treatment

In 1994, researchers found that organic ITCs, such as α-naphthyl ITC, can block chemical carcinogenesis in experimental tumorigenesis. Since then, studies have found that PEITC and SFN can inhibit osteosarcoma, lung cancer, colon cancer, oral squamous carcinoma and PCa (169173). Another study found that ITCs can exert their anti-tumor activity through various mechanisms, including the regulation of phase I and phase II metabolic enzymes in the human body, inhibition of cell growth by causing cell-cycle arrest, induction of cell death, and prevention of metastasis and angiogenesis (174).

Lv et al (171) studied osteosarcoma and found that PEITC can inhibit the growth of osteosarcoma cells by inducing different types of cell death processes, such as ferroptosis, apoptosis and autophagy. Their findings suggested that the reduction in proliferative capacity, induction of ferroptosis and activation of MAPKs in human osteosarcoma cells treated with PEITC primarily occur due to ROS production (73).

Unlike PEITC, SFN can inhibit SCLC. SFN induces cell death in SCLC cells by inducing ferroptosis and inhibiting the mRNA and protein expression of SLC7A11. Therefore, SFN may provide new treatment options for SCLC (74). A study found that SFN can trigger apoptosis and ferroptosis in acute myeloid leukemia cells in a dose-dependent manner. Lower doses stimulate caspase-dependent apoptosis, while higher doses activate ferroptosis, indicated by a decrease in intracellular GSH levels and GPX4 protein expression levels (168).

Mechanisms of ITC-induced ferroptosis

A study on PEITC found that PEITC can induce ferroptosis through its effect on iron metabolism and the generation of ROS. Regarding its effect on iron metabolism, PEITC can upregulate TFR1 and downregulate FTH1, FPN and DMT1, leading to an increase in labile iron. In addition, PEITC can induce GSH depletion to stimulate ROS production and lipid peroxidation (73,171). Furthermore, ITCs can decrease cell survival by increasing ROS production (174).

SFN triggers ferroptosis, indicated by a decrease in intracellular GSH levels, suppression of the expression of GPX4 protein and lipid peroxidation. SFN inhibiting system xCT activity or directly depleting GSH levels, and its inhibitory effect on GPX4 (168). In another study, SFN-induced cell death in SCLC cells was found to be facilitated by ferroptosis and the suppression of the mRNA and protein expression of SLC7A11 (74).

To summarize, PEITC and SFN induce ferroptosis through different mechanisms. PEITC primarily induces ferroptosis by generating ROS, which disrupts iron metabolism. However, SFN mainly induces ferroptosis by modulating the xCT system. The mechanisms of ITCs acting on targets of ferroptosis are illustrated in Fig. 3.

Drug combination and chemical modification of ITCs in cancer therapy. Kasukabe et al (75) conducted a study in which they used PEITC along with cotyledon A (CN-A), a plant growth regulator that effectively induces myeloid leukemia cell differentiation. They found that CN-A and PEITC synergistically induced cell death, mainly by inducing ferroptosis, and the combination of these two agents increased ROS levels. However, the mechanisms underlying the interaction between CN-A and PEITC need to be elucidated (75).

In a study, a hybrid androgen receptor (AR) antagonist containing ITC was designed and synthesized to treat castration-resistant PCa (CRPC). This strategy was combined with the administration of the GSH synthesis inhibitor buthionine sulfoximine to effectively downregulate AR/AR splice variants and induce the removal of iron from CRPC cells. The results showed that the drug combination significantly increased lipid peroxidation and cell viability was effectively rescued by iron chelators, antioxidants or heme oxygenase-1 inhibitors, which indicated that ferroptosis was induced (76).

To summarize, the combination of ITCs can stimulate the induction of iron deficiency anemia. Various researchers have conducted experiments associated with combination therapy and obtained promising results.

Other natural product-induced ferroptosis

Besides the above-mentioned compounds, numerous other natural products are known to induce ferroptosis, but reports on these products are limited. Thus, they were discussed in this chapter to help researchers obtain key information. Others acting on targets of ferroptosis are presented in Fig. 3.

Gallic acid (GA)-induced ferroptosis

GA is present in various commonly consumed foods, including edible herbs and vegetables (175). Numerous studies have shown the inhibitory effects of gallic acid on different types of cancer, including but not limited to lung cancer (176), PCa (177), skin cancer (178), leukemia (179), lymphoma (180), cervical cancer and breast cancer (181). GA is assumed to stimulate cancer cells to undergo apoptosis. This hypothesis is supported by various markers, including mitochondrial fragmentation, the release of cytochrome c from mitochondria into the cytosol, nuclear condensation, DNA damage and activation of caspase-3 (175). Research conducted on various tumor cell lines, including HeLa, H446 and SH-SY5Y, using GA showed that it can inhibit tumor-cell proliferation. This effect is attributed to the mechanisms involving apoptosis, ferroptosis and necrosis (182). In addition, the mixed lineage kinase domain-like protein inhibitor necrosulfonamide can increase the sensitivity of cancer cells to GA; thus exerting a synergistic effect (77). Another study showed that the anti-tumor effect of gallic acid is enhanced under low-intensity laser irradiation. This enhancement occurs through the production of ROS, induction of cell apoptosis and promotion of ferroptosis (78).

Gambogenic acid (GNA)-induced ferroptosis

GNA is a primary bioactive component obtained from Gamboge, which is the dried resin of Garcinia hanburyi Hook. f. (182). GNA has various antitumor activities in vitro and in vivo (183). It can inhibit lung cancer (184), nasopharyngeal carcinoma (185) and melanoma (186). Its mechanism of action involves abnormal autophagy, which mediates cell apoptosis through the AKT signaling pathway and ferroptosis induced by oxidative stress (186). A study found that GNA triggers ferroptosis in TGFβ1-stimulated melanoma cells by modulating the p53/SLC7A11/GPX4 signaling pathway (187).

Piperlongumine (PL)-induced ferroptosis

PL is a potent alkaloid with excellent biological activity. It is primarily derived from the long pepper plant (Piper longum L.). Several studies conducted in vitro and in vivo have illustrated the targeted initiation of apoptosis or programmed cell death by PL in different types of cancer cells, including pancreatic cancer (188), breast cancer (189) and leukemia (190). PL has no anti-proliferative effects on non-transformed cells, which reflects its specificity for cancer cells. Furthermore, a study found that PL triggers cancer cell death, partly by inducing ferroptosis. CN-A and PL, in combination, synergistically trigger the death of pancreatic cancer cells; in this process, CN-A increases the ROS levels stimulated by PL (79).

Albiziabioside A (Alb A)-induced ferroptosis

Alb A is a natural oleanane triterpenoid saponin. It was found to induce apoptosis in malignant melanoma cells through the mitochondria-mediated caspase cascade (191). A study found that structural modifications of Alb A can improve its anti-tumor efficacy by inhibiting the expression of GPX4 and increasing lipid peroxidation, thus inducing ferroptosis in HCT116 cells (80). In another study, a combination treatment with Alb A and pyruvate dehydrogenase kinase inhibitors also led to the induction of ferroptosis (192).

Erianin-induced ferroptosis

A study reported the anti-tumor properties of erianin, a natural compound extracted from Dendrobium chrysotoxum Lindl., in various types of cancer (193). In a groundbreaking study, erianin was found to induce ferroptotic cell death in lung cancer cells, accompanied by the accumulation of ROS, lipid peroxidation and depletion of GSH. The study found that Ca2+/CaM signaling acts as a key mediator of erianin-triggered ferroptosis. Inhibiting this signaling pathway rescued cell death induced by erianin treatment, highlighting its role in the suppression of ferroptosis (81). Another study on erianin also revealed its ability to inhibit the growth of bladder cancer cells by inducing ferroptosis via Nrf2 inactivation (82).

Robustaflavone A (RF-A)-induced ferroptosis

RF-A was isolated from Selaginella trichoclada. RF-A strongly decreases cell viability. In addition, RF-A was found to trigger non-apoptotic cell death in MCF-7 cells via ferroptosis. This outcome involved the upregulation of the expression of voltage dependent anion channel 2 channel protein and the downregulation of the expression of neuronal precursor cell-expressed developmentally downregulated 4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS generation (194).

Solasonine-induced ferroptosis

Studies have investigated the therapeutic effects of solasonine, a steroidal alkaloid extracted from the natural herb Solanum nigrum L. It can inhibit the transcription factor AP-2 alpha/Otubain 1/SLC7A11 axis, thus activating ferroptosis and suppressing the progression of pancreatic cancer cells (195). Another study showed that solasonine induces ferroptosis in HCC cells by disrupting the GSH redox system via GPX4 (196).

β-Elemene-induced ferroptosis

A study found that β-elemene increases the responsiveness of EGFR-mutant NSCLC to erlotinib by eliciting ferroptosis. This mechanism involves upregulation of the long non-coding RNA H19 (83). Another study found that the combination treatment of β-elemene and cetuximab was effective in KRAS mutant colorectal cancer cells. This combination treatment induced ferroptosis and inhibited epithelial-mesenchymal transition, thus increasing sensitivity (23).

Isoliquiritin (Iso)-induced ferroptosis. Iso is a flavonoid glycoside derived from Glycyrrhiza uralensis. A study showed that isoliquiritin exerts its effects by modulating ferroptosis by inhibiting NF-κB signaling. Iso can also alleviate doxorubicin resistance in breast cancer (84).

Quercetin-induced ferroptosis

Quercetin is a flavonoid derived from plants and is abundant in various fruits and vegetables, including grapes, apples, onions and green leafy vegetables. It not only has antioxidant, anti-inflammatory, anti-fibrotic and antiviral effects but also has high efficacy in suppressing the proliferation of different types of cancer (197). Two studies have found that quercetin facilitates the degradation of lysosome-dependent ferritin, leading to the liberation of free iron, thus initiating ferroptosis (85,86).

Conclusions and perspectives

Certain researchers argue that ferroptosis needs to be more clearly distinguished from necrosis (22). Natural products have varied structures and different mechanisms of action to induce ferroptosis. The development and research of natural products to induce ferroptosis can provide novel and deeper insight into ferroptosis. For instance, the mechanisms by which ARTCs, such as tanshinone and ITCs, induce ferroptosis are diverse. Studying the role of these compounds in inducing ferroptosis may help address some of the unresolved questions. Numerous studies have investigated the role of ARTCs in ferroptosis. These compounds have clear effects and great potential as promising inducers of ferroptosis for development and utilization. However, the relationship between their role in inducing ferroptosis and their anti-tumor effects needs to be elucidated. Studies investigating the mechanism of action of ferroptosis inducers prioritized the key drivers and the GPX4 pathway, whereas other ferroptosis defense mechanisms discussed in this review were paid lesser attention to. Thus, further research is needed to understand these aspects.

Combination treatment is generally performed to reduce toxicity and drug resistance. Numerous studies have assessed the combined application of natural products with ferroptosis-inducing effects and first-line anti-tumor drugs, such as the combined administration of ARTCs with sorafenib and cisplatin. Further research on such combination treatment strategies is expected to increase. Studies on the combination of ferroptosis inducers with first-line anti-tumor drugs may become more prevalent. The combination of drugs with multiple mechanisms of action may act synergistically and reduce drug toxicity. Ferroptosis inducers promote ferroptosis by reversing resistance and allowing first-line anti-tumor drugs to continue exerting their effects.

The structures of natural products related to ferroptosis induction are rich and diverse. Thus, they can be used as a resource pool for comprehensive research on drugs. These structures provide valuable and novel information on ferroptosis and drug development. Improving the structure of these products to enhance their ability to induce ferroptosis can help develop more effective drugs. Researchers believe that compounds with an inner peroxide structure, including ARTCs, have strong ferroptosis inducing ability. They can individually or synergistically induce ferroptosis. Based on this finding, structural improvements may be implemented as an effective strategy to develop and screen potent ferroptosis-inducing compounds.

Acknowledgements

Not applicable.

Funding

Funding: This work was supported by the National Natural Science Foundation of China (grant nos. 81960739 and 82360797), the Joint Application and Basic Research Foundation of Kunming Medical University & Science and Technology Department of Yunnan Province of China (grant no. 202401AY070001-209), the Research Project on Undergraduate Educational and Teaching Reforms in Yunnan Province (grant no. JG2023001) and the Foundation of the Department of Education of Yunnan Province of China (grant no. 2024J0150).

Availability of data and materials

Not applicable.

Authors' contributions

XN: Conceptualization, writing-original draft, supervision, writing-review & editing. LL: Writing-original draft. DML and JQH: Literature review. LZ and YPZ: Conceptualization, supervision, writing-review & editing. All authors have read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

ACSL4

acyl-CoA long chain synthetase family member 4

ALOXs

arachidonic acid lipoxygenases

ARE

Nrf2-antioxidant response element

ARTCs

artemisinin compounds

ATS

artesunate

CHAC1

glutamylcyclotransferase 1

CPT

cryptotanshinone

Cys

cysteine

DFO

deferoxamine

DHA

dihydroartemisinin

DHT I

dihydrotanshinone I

DT

dihydroisotanshinone I

ER

endoplasmic reticulum

FIN

ferroptosis inducer

FTH1

ferritin heavy chain

FTL

ferritin light chain

GA

gallic acid

Glu

glutamate

GNA

gambogenic acid

GPX4

GSH peroxidase 4

GSH

glutathione

ITCs

isothiocyanates

Iso

isoliquiritin

Keap1

Kelch-like ECH-associated protein 1

LIP

labile iron pool

NCOA4

nuclear receptor co-activator 4

Nrf2

nuclear transcription factor erythroid-related factor

PEITC

phenethyl isothiocyanate

P-gp

P-glycoprotein

PL

piperlongumine

POR

cytochrome P450 oxidoreductase

PUFAs

polyunsaturated fatty acids

ROS

reactive oxygen species

SFN

sulforaphane

SLC7A11

solute carrier family 7 member 11

Tan I

Tanshinone I

Tans

Tanshinone and its derivatives

TF

transferrin

TFR

transferrin receptor

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September-2024
Volume 52 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Copy and paste a formatted citation
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Spandidos Publications style
Na X, Li L, Liu D, He J, Zhang L and Zhou Y: Natural products targeting ferroptosis pathways in cancer therapy (Review). Oncol Rep 52: 123, 2024.
APA
Na, X., Li, L., Liu, D., He, J., Zhang, L., & Zhou, Y. (2024). Natural products targeting ferroptosis pathways in cancer therapy (Review). Oncology Reports, 52, 123. https://doi.org/10.3892/or.2024.8782
MLA
Na, X., Li, L., Liu, D., He, J., Zhang, L., Zhou, Y."Natural products targeting ferroptosis pathways in cancer therapy (Review)". Oncology Reports 52.3 (2024): 123.
Chicago
Na, X., Li, L., Liu, D., He, J., Zhang, L., Zhou, Y."Natural products targeting ferroptosis pathways in cancer therapy (Review)". Oncology Reports 52, no. 3 (2024): 123. https://doi.org/10.3892/or.2024.8782