1. Introduction

1.4. NRF2 signaling pathway in cancer

The significance of NRF2 in cancer is widely recognized. It is crucial to understand its negative regulator, KEAP1, which modulates NRF2 to decrease its cellular expression and effectively control metabolic balance [91]. The KEAP1 activity is closely correlated with cellular levels of NRF2 protein after normal or low/moderate responses to stressful situations to monitor cellular antioxidant responses, as well as detoxification responses involved in cancer prevention and treatment [92].Understanding these regulators would enable researchers to channel NRF2's footprint into a more targeted approach aiming to completely eradicate tumors, while also addressingits pro-oncogenic effects, most of which are associated with the "dark side" of NRF2, clearly linked to the metastatic behavior of tumor cells [93].

Numerous studies have shown that the activation of NRF2 preserves the health of cells exposed to diverse toxic components and illnesses; it has also been observed that the over-activation of NRF2 promotes tumor development and protects tumor cells from oxidative injury, which can further induce chemo-resistance [94]. The elevated levels of NRF2 observed in cancer contributes to an increased expression of key metabolic enzymes including transketolase (TKT), phosphogluconate dehydrogenase (PGD), glucose 6-phosphate dehydrogenase (G6PD), and several others [95]. This heightened activity of glucose metabolic enzymes promotes the production of purine and amino acids, along with the regeneration of the NADPH pool through the pentose phosphate pathway (PPP). Consequently,, there is a reconfiguration of metabolic pathways to faciliate cellular growth and enhance antioxidant capacity [96].

As a key regulator in carcinogenesis, the cell cycle is closely linked to Nrf2 over-activation, as Nrf2 deficiency leads to arrest in the G2/M phase of the cell cycle. It appears that Nrf2 is a controller in the regulation of the cell cycle through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling [97]. Some studies have indicated that the over-expression of NRF2 induces the phosphorylation of AKT, glycogen synthase kinase-3 (GSK3), PPP, and KRAS activation[98,99]. In addition, cooperation between the PI3K/AKT and KRAS/MAPK pathways can lead to an increase in the anabolic pathways efficiency, the inhibition of the apoptosis, and induce survival and self-renewal inducement in cancer stem cells (CSCs) by anti-apoptotic factor B-cell lymphoma 2 (Bcl-2) [100]. These mechanisms contribute to the development and progression of cancer[101].

Furthermore, the activation of Nrf2 is associated with the inhibition of chronic inflammation, a factor linked to cancer[102]. Inthe absence of Nrf2, certain pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2 (COX-2), are increased significantly [103]. The iNOS can produce nitric oxide, which contributes in inflammation and tumor development[104]. It also can cause mutagenesis and DNA degradation [105]. The TNF-α is one of the main cytokines regulating the progression of inflammation through different signaling pathways [105,106]. Additionally, Cox-2 serves as another regulator of inflammatory diseases [106] (Figure 1).

Furthermore, Nrf2 regulates the fundamental expression of mouse double minute 2 homolog (Mdm2), a potential repressor of tumor suppressor p53 [107]. Similarly, the overexpression of the transcription factor Nrf2 secondarily down-modulates TP53 and enhances cancer cell self-renewal by inhibiting p53-linked apoptotic death signals [108]. In an investigation involving human refractory ovarian cancer cells, the elevated expression of NRF2 was observed compared to the non-resistant cell line, and NRF2 knockout by siRNA reintroduced drug response. In addition, chemical NRF2 induction delivered a survivability nature to immortalize neuroblastoma cell lines responding to tumor medications such as etoposide, cisplatin, and doxorubicin [109,110]. Based on these findings,, Cho and his team confirmed that the knockdown of NRF2 through siRNA treatment enhanced the cisplatin sensitivity in ovarian cancer cells [109]. Likewise, Long-term stimulation of NRF2 has been found to impair efficacy of combined drug and radiation treatment in human respiratory tract cancer cells. Conversely, lower levels of NRF2 increased the cellular response to ionizing radiation and cytotoxic drugs [111]. The above results suggest that Nrf2 function alone or in combination with complementary drugs can be considered a productive method to improve the response of metastatic cells to chemotherapy. Moreover, recent investigations highlight the role of Nrf2 in malignancy, where functional Nrf2 promotes lung cancer metastasis by preventing the degradation of the heme-binding Bach1 transcription regulator [112].

The overproduction of NRF2 triggers cell growth and metastasis in breast cancer by activating the RhoA gene expression along with its downstream effectors [113]. The significant role of NRF2 in proliferation and invasion is also observed in hepatocellular carcinoma, where it regulates the post-transcriptional expression of target genes such as metalloproteinase-9 (MMP-9) and BCL-XL transcripts [93]. Recent findings have highlighted that, beyond facilitating tumor advancement, UPR activation can also play a role in the development of chemo resistance (as depicted in Table 1) [114,115,116,117]. Silencing all three branches of the UPR has been linked to the restoration of sensitivity in previously resistant cancer cells [116,118,119]. Rapidly dividing tumor cells might exploit distinct UPR branches to complement their pre-existing mechanisms of chemo-resistance. Furthermore, the targeted activation of a specific UPR arm may be intertwined with other inherent mechanisms of chemo-resistance [24].

Antioxidants play a complex role in cancer therapy, resembling a double-edged sword. While they can potentially protect healthy cells from the damaging effects of treatments like chemotherapy and radiation by neutralizing harmful free radicals, they might also inadvertently shield cancer cells from these therapies, reducing their effectiveness. This duality underscores the need for a balanced approach when considering the use of antioxidants in cancer treatment strategies [120]. This regulation exhibits the dual character of ROS: at low concentrations, it acts as a critical second intracellular messenger in various signal transduction pathways, whereas at high concentrations, through a change in gene expression, cells try to confront stress by converting to antioxidant response [27].

As mentioned earlier, the activation of NRF2 signaling has gained attention for its potential to mitigate the adverse effects of chemotherapy. This pathway plays a protective role by shielding cells from oxidative harm. However, inhibiting oxidative-induced cell death through NRF2 activation can lead to the development of chemo-resistance in cancer cells. Evidently, NRF2 might contribute to the promotion of tumor-initiating cell lineage, consequently giving rise to chemo resistance. [35]. Increased NRF2 expression has been studied in various cancer types, including head and neck, lung, epithelial, gastric, and pancreatic cancer [93,121,122]. It has been found that elevated NRF2 expression can lead to resistance to radiation, 5-fluorouracil, and cisplatin, possibly through the induction of antioxidants [123]. Therefore, there may be a need to consider inhibiting the NRF2 pathway during chemotherapy [34].

Table 1. Molecular Mechanisms involved in chemo-resistance.

Table 1. Molecular Mechanisms involved in chemo-resistance.

Underlying molecular mechanism	Cellular effect	Reference
Transporter pumps (ABC proteins, SERCA, V-ATPase)	These proteins exhibit elevated expression levels in chemo-resistant cancer cells and play a role in the development of drug resistance.	[124,125,126]
Oncogenes EGFR	The overexpression of EGFR triggers the activation of NF-κB and STAT3, which subsequently leads to the development of chemo-resistance and unfavorable treatment outcomes.	[127]
KRAS	Oncogenic KRAS promotes drug resistance via upregulation of the cell protective stress response gene, NRF-2, at the transcriptional level.	[128]
(PI3K)/Akt	AKT involves in apoptosis, migration, and proliferation.	[129]
NF-кB	Following activation, NF-κB translocates to the nucleus, elevating the expression of BCL-2, BCL-XL, XIAP, survivin, and AKT, thereby contributing to accelerated tumorigenesis, increased aggressiveness, drug resistance, and induction of EMT.	[130]
ERKs	ERKs are recognized for their role as activators of various transcription factors, including ETS Like1, along with downstream protein kinases. These factors are closely linked to processes such as cell proliferation, drug resistance, and apoptosis.	[131]
Oncogenic Viruses	Viral onco-proteins contribute to chemo-resistance through multiple mechanisms, including the regulation of cellular transporters and drug targets, modulation of signaling pathways involved in drug-induced cell death responses, and activation of pathways that counteract the effects of drugs.	[120]
Rb	Oncogenic p53 causes chemo-resistance of cancer cells by increasing the expression of MDR-1.	[132,133,134,135,136,137]
CKIs	These mechanisms involve inducing cell cycle arrest and activating DNA repair processes	[138,139,140]
PTEN	Increase apoptosis, regulating cell cycle progression.	[141,142]
BRCA1	Reduction of cell proliferation, migration, survival and cell size, Regulating transcription, cell cycle checkpoint, DNA repair, and apoptosis.	[143,144,145,146]
Mitochondrial alteration SERCA	Bcl-2 and Bcl-xL contribute to heightened drug resistance, while reducing their expression enhances the cytotoxic impact of cisplatin and gemcitabine. Moreover, the level of survivin expression was found to be linked to the degree of cisplatin resistance in gasteric cancer cells.	[147]
V-ATPase	Somatic mutations occurring in the mitochondrial genome (mtDNA) of cancer cells lead to impaired mitochondrial function, which in turn contributes to the development of chemo-resistance.	[148]
DNA repair	BER and NER can confer the resistance to chemo drugs that target DNA. RAD51, a crucial participant in homologous recombination during double-strand break (DSB) repair, being overexpressed, serves as a marker for resistance to Cisplatin (CDDP) in non-small cell lung cancer (NSCLC). Similarly, elevated expression of ERCC1, a component of the nucleotide excision repair (NER) pathway, is associated with resistance to CDDP in both human hepatocellular carcinoma (HCC) cell lines and specimens.	[149,150,151]
Autophagy	In tamoxifen-resistance breast cancer cells, SAHA, as a HDAC inhibitor, can induce autophagic cell death and reduce tumor growth. Despite the challenges about the anticancer and pro-survival function of autophagy, in vitro and in vivo research has been more confirmed that autophagy could be considered as a facilitator of cancer chemo-resistance. In NSCLC cells, autophagy inhibition using Chloroquine, before paclitaxel treatment, prevents drug resistance.	[14,152,153]
UPR	CSCs and actively dividing tumor cells might exploit distinct branches of the UPR to reinforce their pre-existing mechanisms of chemo-resistance. Notably, the suppression of all three UPR branches—GRp78, ATF6, ATF4, and XBP1s—has shown a correlation with the restoration of sensitivity in chemotherapy-resistant cancer cells.	[24,116,117,118,119]
EMT	EMT has been identified as a promoter of chemo-resistance against the DNA alkylating agent cyclophosphamide and the DNA synthesis inhibitor gemcitabine. Specifically, the attenuation of Snail or Twist has been linked to increased sensitivity to chemotherapy.	[154]
Cancer stemness	Cancer stem cells (CSCs) resist chemotherapy by increasing the levels of P-glycoprotein, ABCG2, BCL-2, and survivin. Recent findings highlight NRF2's role in preserving stemness, intensifying tumorigenicity, and initiating chemo-resistance within CSCs.	[155,156]
Regulatory redox network	The mechanisms of ROS-mediated acquired chemo-resistance include autophagy, ER stress, overcoming cell cycle arrest, and enhancing epithelial to mesenchymal transition or cancer stem-like cells. Numerous chemotherapy agents, including cisplatin, doxorubicin, etoposide, paclitaxel, and bortezomib, induce cancer cell death by elevating ROS levels. Adjusting intracellular antioxidant levels holds potential therapeutic benefits but can be complex. While antioxidants may impede chemotherapy efficacy by scavenging ROS, they can also trigger chemotherapy-related toxicity, highlighting a delicate balance.	[12,120,157]

2. Redox regulatory network involved in the induction of autophagy/UPR and tumor chemo-resistance

3. NRF2 controls UPR and proteostasis

4. Evidence show overexpression of NRF2 promotes post-initiation stages of cancer

4.2. Targeting of Nrf2 Signaling to fight Chemo-resistance: NRF2 inhibitors

Regarding the distinct NRF2 levels between cancer and normal cells, inhibiting NRF2 activity with small molecular inhibitors might be a safe and promising strategy to overcome multidrug resistance in cancers. For example, sequential therapy of breast cancer cells with vitamin C and quercetin has been found to reduce the expression of NRF2 at both the mRNA and protein levels [289]. Additionally, combination therapy with vitamin C and quercetin has been reported to enhance the cytotoxic feature of chemotherapeutic drugs in breast cancer cells as compared with the drug treatment alone [290].Developing novel and potent NRF2 inhibitors is undoubtedly a challenging task, although only a small number of NRF2 inhibitors have been proposed for further preclinical experiments. [291].

There is a large number of synthetic molecules and flavonoids that inhibit Nrf2, but in this review, we only focused on NRF2 inhibitors studied based on data from various preclinical and experimental models. Studies have frequently pointed to the inhibition of the NRFrf2 pathway as a promising therapeutic choice for the treatment of cancer, which requires more investigation and authentication in the clinical settings. The inhibitors we have discussed, as outlined in (Table 2), exhibit a range of inhibitory mechanisms. These mechanisms include the inhibition of overall protein synthesis (brusatol, halofuginone, camptothecin/CPT), disruption of NRF2 nuclear translocation (trigonelline, ATRA), inhibition of DNA binding (ML385), suppression of associated kinase pathways (clobetasol propionate, flavonoids), initiation of NRF2 degradation (clobetasol propionate), or an effect that remains undisclosed (triptolide, IM3829, AEM1).

The use of this approach is exemplified by well-known instances such as the quassinoid brusatol [292], as well as other compounds like retinoic acid [261] and natural flavonoids such as luteolin, apigenin, chrysin, and wogonin [293,294,295,296]. Brusatol, derived from the natural product of Brucea javanica, functions as an NRF2 inhibitor, validated through a stable ARE-luciferase reporter gene cell line known as MDA-MB-231-ARE-Luc [228]. Recent studies have shown that it effectively reduces NRF2 protein levels across various cell lines, including MDA-MB-231, Hela, Ishikawa, and SPEC-2, while NRF2 mRNA levels remain unaffected. Furthermore, brusatol does not impact KEAP1 protein and mRNA levels. Notably, it sensitizes A549 cells and xenografts to a range of chemotherapeutic drugs including carboplatin, 5-fluorouracil, etoposide, and paclitaxel [292]. Histological investigation showed that brusatol treatment decreased the expression of antioxidant genes such as NRF2, solute carrier 7A11 (SLC7A11), GCLC, and GCLM in a xenografted glioma model [297].

Table 2. Research Summary on Nrf2-ARE Inhibitors in Preclinical and Experimental Models.

Table 2. Research Summary on Nrf2-ARE Inhibitors in Preclinical and Experimental Models.

Classification and origins	Compound	Structure	Dose and time	Mechanism	Model and effect	Refs.
Brucea javanica Plant	Brusatol (Bru)		2 mg/kg, five times for 16 days via intraperitoneally	↓ NRF2/GSH axis	↓tumor mass ↓NRF2, SLC7A11, GCLC, and GCLM expression Six-to-eight-week-old NSG mice	[298]
Flavonoid	Luteolin (Lut)		40 mg/kg BW/day; 14 days	Unclear	↓NRF2 protein levels in mouse liver and intestine (C57BL/6, Male, 6 weak old)	[293]
Flavonoid	Apigenin (Api)		In vivo: 50 mg/kg BW/day; every 3 days for 7 times	PI3K/Akt pathway: ↓p-Akt	↓tumor size in male BALB/c nude mice (aged 5 weeks) that were implanted with BEL-7402 cells; ↓level of NRF2 protein	[294]
Flavonoid	Chrysin (Chry)		40 and 80 mg/kg/day by oral gavage; once a day, 5 times per week	↓ERK/NRF2 signaling pathway	↓Tumor size of mice (male BALB/c athymic nude mice, 4–6 weeks) ↓translocation of NRF2 into the nucleus and ↓ expression of (HO-1) and NQO-1	[295]
Flavonoid	Wogonin (Wog)		40 mg/kg intravenously, once every other day for 30 days	↓NF-κB/NRF2 pathway	NOD/SCID immunodeficient mice (aged 5–6 weeks) ↓ nuclear NF-κB p65, p-Stat3 and NRF2 expression and ↓phosphorylation of IKKα and IκBα ↓NF-κB p65 and NRF2 expression in spleen	[296]
A traditional Chinese medicine	triptolide		0.25 mg/kg, by intraperitoneal every other day for 10 days	transcriptional regulation of NRF2	↓Tumor growth and weight C57BL/6 mice (6–8 weeks, male) ↓NRF2 and downstream genes Gclc and Gclm increases the chemosensitivity of xenograft tumors to epirubicin	[299]
An alkaloid	Trigonelline (Trig)		0.02 mg/kg intraperitoneally for 21 days	↓ a nuclear level of activated NRF2 protein	↓tumor growth and weight 8-week-old female SCID–beige mice ↑responsiveness of various cell lines to both anticancer drugs and apoptosis induced by TRAIL.	[300]
Vitamin derivative	all-trans-retinoic acid		10 µM, 48h 40 mg/kg, three times weekly via intraperitoneally	↓NRF2/POMP axis	↓cell viability, purified CD138+ plasma cells from patients with myeloma ↓tumor growth 6-week-old non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice	[261]
Aniline-based compound	IM3829 (4-(2-Cyclohex-ylethoxy) aniline)		5mg/kg/day), intraperitoneally for 4 days	↓NRF2-binding activity and expression of NRF2 target genes, increase ROS accumulation in irradiated cell	↓tumor growth, without changes in body weight, Five-week, female, athymic BALB/c nude mice	[301]
A probe molecule that binds to Nrf2	ML385		30 mg/kg daily Monday to Friday), intraperitoneally for 3 weeks	blocks NRF2 transcriptional activity	↓tumor growth, athymic nude mice, ↓NRF2, NQO1, and ABCG2 expression	[302]
A chemical substance	ARE expression modulator 1 (AEM1)		50 mg/kg, BW; twice a day for 10 days	Unclear	↓Tumor growth of mice which were implanted with A549 cells (Nude mice, Male, 6 wk old)	[303]
A febrifugine derivatives	halofuginone		0.25 mg/kg, every day intraperitoneally	Inducing a cellular amino acid starvation response that repressed protein level of NRF2	↓tumor growth, 6–8-week-old male nude mice, enhances the anticancer effects of cisplatin. without severe toxicity	[304]
Corticosteroid drug	Clobetasol propionate		CP (0.5 or 1 mg/kg, n = 5 per group) were intraperitoneally injected every 2 days (3 days per week) for 40 days.	↓NRF2 in a GR and GSK3-dependent manner	Balb/c-nu mice (6–8 weeks). ↓NRF2 and the expression of its key targets in KEAP1 mutant NSCLCs and induction of oxidative stress. ↓tumor growth and shrinkage of tumor size	[305]
Purified from Streptomyces sp. 3728-17 strain	K-563		100 mg/kg, subcutaneously to the mice twice a day for 1 day	↓Keap1/NRF2 pathway	Male severe combined immunodeficient (SCID) mice, 5 weeks’ old ↓expressions of Keap1/NRF2 pathway Targeted genes (HMOX1, GCLC, GCLM,AKR1C1, ME1, NQO1, and TXNRD1)	[306]
Anti-tumor drug	Camptothecin		CPT (3 mg/ kg body weight) were intraperitoneally (IP) injected twice a week for a total of three times.	↓NRF2–ARE pathway activity	↓tumor growth BALB/Cnu/nu mice (4–6 weeks, male). Sensitization of a variety of cancer cells and a xenograft hepatocellular carcinoma model to chemotherapeutic drugs	[307]
Type 2 diabetes drug	Metformin		200 μg/mL, diluted in drinking water and administered for day 22	↓NRF2, HO-1, KI-67 and PCNA expression	↓tumor growth, Female BALB/C nude mice (6-8 weeks of age) enhancing the anti-cancer effect of EGCG on NSCLC xenografts	[308]
Cardiac glycoside drug	Digoxin		0.1 mg/kg, daily, i.g for 24 days	↓Activity of NRF2 through suppressing PI3k/Akt signaling pathway	↓tumor growth In female BALB/c nude mice (aged 6 weeks, weighing 18 ± 2 g), the resistance to gemcitabine was effectively reversed by inhibiting NRF2 in SW1990/Gem and Pac-1/Gem cells.	[30]

These compounds possess drawbacks like lack of specificity and potential off-target effects. For instance, brusatol exhibits a global protein translation suppression effect [228]. Luteolin (3′,4′,5′,7-tetrahydroxyflavone) reduces both NRF2 mRNA and protein levels in A549 cells by promoting NRF2 mRNA degradation, sensitizing them to antitumor drugs. In mice, luteolin treatment decreases NRF2 protein levels and reduces tumor size in the liver and intestine [293]. Apigenin (4′, 5, 7-trihydroxyflavone) and chrysin (5, 7-dihydroxyflavone) also decrease NRF2 mRNA and protein levels, rendering hepatocellular carcinoma BEL-7402 cells more responsive to the anti-tumor drug doxorubicin. Recent research highlights that apigenin and chrysin's NRF2-suppressive effects stem from inhibiting the PI3K/AKT pathway. Notably, apigenin treatment induces tumor size reduction in mice implanted with hepatocellular carcinoma cells. [294].

Notably, apigenin and chrysin exhibit direct inhibition of the PI3K/AKT pathway, a critical regulator of cancer cell proliferation [228,294]. Their distinct actions on cancer cells compared to normal cells, along with their low toxicity, make them promising candidates for cancer treatment. Another compound, wogonin (5, 7-dihydroxy-8-methoxyflavone), derived from the traditional Chinese herb Scutellariae radix, has emerged as an NRF2 inhibitor methoxyflavone) [228]. Wogonin effectively counteracts drug resistance in various cell lines, including human breast adenocarcinoma MCF-7/DOX, human myelogenous leukemia K562/A02, and HepG2 cells by suppressing NRF2 mRNA and protein expression. Notably, it enhances the anticancer effects of Adriamycin in leukemia by inhibiting pY705-Stat3 and NRF2 signaling pathways[296].

Triptolide, an agent from traditional Chinese medicine, has been proven to effectively inhibit the expression and transcriptional activity of NRF2 in various cancer cell types, including non-small cell lung cancer (NSCLC) and liver cancer cells. This suppression of NRF2 activity leads to enhanced chemosensitivity of cancer cells to antitumor drugs both in laboratory settings and in a xenograft tumor model of lung carcinoma cells. [299].

Trigonelline, an alkaloid found in various plants and coffee, has the potential to enhance cell susceptibility to apoptosis by inhibiting the nuclear translocation of NRF2. This action is accompanied by a reduction in proteasomal gene expression and proteasome activity[228]. The favorable safety profile of this natural coffee constituent in both regular consumption and therapeutic applications suggests its viability for combination therapy in pancreatic and other types of cancers.[300]. All-trans-retinoic acid (ATRA), also identified as tretinoin, is a vitamin in the retinoid family of medicines [228]. As an NRF2 inhibitor, ATRA diminishes cellular levels of NRF2 and boosts the anti-prolife\rative and pro-apoptotic actions of bortezomib in resistant cells while reducing proteasome activity. The combination therapy with all-trans-retinoic acid plus bortezomib exhibited great activity versus primary patient samples and in a mice-bearing bortezomib-resistant myeloma model [261]. A number of research teams have purified several chemical libraries for small molecules that hinder NRF2 activity with various cell-dependent reporter analyses [228]. Employing ARE-directed luciferase assays, researchers found compounds such as 4-(2-cyclohexylethoxy) aniline (IM3829) [301], ML385 [302], halofuginone [304], and clobetasol propionate [305] were powerful suppressors of NRF2 activity.

IM3829 stands as the first synthetic NRF2 inhibitor, as revealed by Song et al. Their pursuit involved screening a synthetic compound library of 8000 substances through a HEK293 cell-based ARE-luciferase reporter assay, leading them to identify IM3829 [4-(2-cyclohexylethoxy) aniline] as a small-molecule NRF2 blocker [228]. This compound was found to decrease the mRNA levels of NRF2 and its target genes, HO-1 and NQO1, in both H1229 and A549 cells. In tandem with irradiation (IR) therapy, IM3829 inhibited the nuclear translocation of NRF2, increased ROS levels in lung cancer cells, and significantly delayed tumor growth in H1299 and A549 xenograft models, surpassing the effects of IR-only treatment or Dimethyl sulfoxide (DMSO). Overall, IM3829 holds potential as a radiosensitizer for non-small cell lung cancer (NSCLC) [301]. Moving on, ML385 selectively suppresses the growth of KEAP1-mutated NSCLC A549 and H460 cells while leaving normal lung epithelial BEAS2B cells, possessing wild-type NRF2 and KEAP1, unaffected. Additionally, ML385 enhances the sensitivity of NSCLC cells to the chemotherapeutic drug carboplatin both in vitro and in vivo. [302].

In a recent study, a compound called ARE expression modulator 1 (AEM1) has been identified as a potent suppressor of antioxidant response element (ARE) activity. It effectively reduces ARE-luciferase activity in 3T3 cells and downregulates HO-1 expression in A549 cells with an IC50 of 650 nM. AEM1 also enhances the susceptibility of A549 cells to the cytotoxic effects of chemotherapy drugs like etoposide, 5-fluorouracil, and doxorubicin. In vivo experiments have shown that AEM1 can inhibit tumor growth in an A549 xenograft-model. [303].

Halofuginone, derived from febrifugine and known for its low toxicity, has been employed as an animal antibiotic [309]. It also demonstrates a dose-dependent repression of NRF2 function and enhances the effectiveness of cisplatin in fighting cancer in vivo. Similar to brusatol, halofuginone blocks NRF2's protein translation [304]. Another instance is clobetasol propionate (CP), which notably reduces NRF2 activity to 40% at a concentration of 1 nM. Treating of KEAP1 mutant cells (H2228 and A549) with CP results in decreased NRF2 target gene expression and increased accumulation of reactive oxygen species (ROS). Furthermore, the combination of CP and rapamycin has been observed to effectively hinder the growth of KEAP1-mutated tumors both in vitro and in vivo [305].

Another study investigated a newly discovered inhibitor of the KEAP1/NRF2 pathway, K563, obtained from Streptomyces sp [228]. K563 was found to hinder the expression of downstream genes and proteins related to this pathway, leading to reduced glutathione production and increased reactive oxygen species in A549 cells. It also exhibited similar effects in cancer cells with mutated KEAP1 or NRF2 genes. In vivo experiments on xenograft mice with A549 cells showed that K563 effectively suppressed the KEAP1/NRF2 signaling pathway within lung cancer tumors. [306].

CPT, known for its role as a topoisomerase inhibitor in the treatment of gastrointestinal and head and neck cancers, has also emerged as a potential NRF2 inhibitor for anticancer purposes. Chen and colleagues introduced CPT as a novel compound that can block NRF2 activity. Through this action, CPT sensitized a range of cancer cells (HepG2, SMMC-7721, A549) and even a xenograft model of hepatocellular carcinoma to various chemotherapeutic agents like As2O3, epirubicin, fluorouracil, and cisplatin. The inhibition of NRF2 by CPT specifically contributed to enhanced chemosensitivity in HepG2, A549, and SMMC-7721 cells[307].

Metformin, a traditional medication for diabetes management, has been found to impede the advancement of cancer. It inhibits the expression of HO-1 and amplifies the anticancer effects of EGCG by augmenting levels of reactive oxygen species. In a particular investigation, the size of transplanted tumors subjected to the combined treatment of metformin and EGCG exhibited reduction in comparison to the control groups. Metformin heightens the susceptibility of non-small cell lung cancer (NSCLC) cells to EGCG treatment by obstructing the NRF2/HO-1 signaling pathway. [308].

In an experimental study, the potent cardiac glucoside digoxin was found to effectively counteract drug resistance to gemcitabine in SW1990/Gem and Pac-1/Gem cells by inhibiting NRF2. Digoxin achieved this by blocking NRF2 through the suppression of the PI3K/AKT signaling pathway[30]. Given NRF2's pivotal role in cancer hallmarks, targeting this transcription factor appears to be a promising therapeutic strategy. While NRF2 activators could potentially prevent chemical carcinogenesis, inhibiting NRF2 holds promise for cancer treatment. Despite challenges in developing safe, potent, and specific NRF2 inhibitors due to NRF2's dual nature, extensive efforts have been dedicated to this area with limited success thus far. It is anticipated that upcoming years will clarify NRF2's potential as both a prognostic biomarker and a therapeutic target within cancer therapy.

5. Conclusion

Abbreviations

References

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