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Cited by 21Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer and biochemical research

20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells

Open access
Shuvalov, Oleg, Kirdeeva, Yulia, Fefilova, Elizaveta, Netsvetay, Sofia, Zorin, Mark, Vlasova, Yulia, Fedorova, Olga, Daks, Alexandra +2 more·2023·Metabolites
DOI 10.3390/metabo13050656PMC PMC10223942
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Abstract

20-Hydroxyecdysone (20E) is an arthropod hormone which is synthesized by some plants as part of their defense mechanism. In humans, 20E has no hormonal activity but possesses a number of beneficial pharmacological properties including anabolic, adaptogenic, hypoglycemic, and antioxidant properties, as well as cardio-, hepato-, and neuroprotective features. Recent studies have shown that 20E may also possess antineoplastic activity. In the present study, we reveal the anticancer properties of 20E in Non-Small Cell Lung Cancer (NSCLC) cell lines. 20E displayed significant antioxidant capacities and induced the expression of antioxidative stress response genes. The RNA-seq analysis of 20E-treated lung cancer cells revealed the attenuation of genes involved in different metabolic processes. Indeed, 20E suppressed several enzymes of glycolysis and one-carbon metabolism, as well as their key transcriptional regulators—c-Myc and ATF4, respectively. Accordingly, using the SeaHorse energy profiling approach, we observed the inhibition of glycolysis and respiration mediated by 20E treatment. Furthermore, 20E sensibilized lung cancer cells to metabolic inhibitors and markedly suppressed the expression of Cancer Stem Cells (CSCs) markers. Thus, in addition to the known beneficial pharmacological activities of 20E, our data uncovered novel antineoplastic properties of 20E in NSCLC cells.

AI snapshot

Written from the paper’s full text.

TL;DR

20-Hydroxyecdysone (20E) reduces ROS, induces antioxidant-response genes, and suppresses glycolysis, respiration, one-carbon metabolism, and cancer stem cell markers in NSCLC cell lines. It also synergizes with metabolic inhibitors, suggesting potential antineoplastic adjuvant activity.

Key findings

  • 20E suppressed intrinsic ROS in H460, H1299, and A549 cells: 0.1 µM reduced ROS by up to 20%, while other concentrations reduced ROS by 30–43%; after 24 h, ROS remained suppressed by 20–25%.
  • RNA-seq of 20E-treated H460 cells found 619 down-regulated and 61 up-regulated genes; 20E suppressed glycolysis and one-carbon metabolism enzymes and regulators including HK2, LDHA, SHMT2, MTHFD2, c-Myc, and ATF4.
  • Seahorse profiling showed 20E inhibited respiration more than glycolysis in H460 cells (respiration up to two-fold, glycolysis up to 30%); in H1299, respiration and glycolysis were suppressed by ~25% and ~20%, and in A549 by 30% and 25%, respectively. ATP levels were reduced up to 2.5-fold.
  • 20E alone only slightly suppressed growth (10–15%), but showed synergy (CI < 1) with 2-DG, metformin, 3-BP, 5-FU, and gemcitabine, and significantly inhibited expression of CSC markers ALDH, CD44, Oct4, c-Kit, and Nestin.

Methods

  • NSCLC cell lines A549, H1299, and H460 were treated with 20E across concentrations (0.01–100 µM) and assessed by ROS flow cytometry, RT-PCR, Qiagen RT2 Profiler oxidative stress array, RNA-seq, Western blot, Seahorse energy profiling, ATP assay, MTT, colony formation, cell cycle, annexin V, and spheroid CSC-marker assays.
  • RNA-seq was performed on H460 cells treated with 10 µM 20E for 24 h; differential expression used DESeq2 with adjusted p < 0.05.
  • Drug synergy was calculated from MTT results using CompuSyn; survival analysis used KM Plotter on a dataset of 1925 lung cancer patients. Statistical analysis used one-way ANOVA with Dunnett’s post hoc test.

Limitations

  • The paper states that translation of the in vitro anticancer effects into the clinic remains uncertain and that further investigations are warranted.
  • The paper notes a biphasic effect, with 100 µM 20E sometimes producing lesser effects than lower concentrations, and suggests pleiotropic/multiple targets rather than a single defined receptor mechanism.
  • Evident from the text: the study is limited to NSCLC cell lines, with no in vivo tumor models; RNA-seq was performed only in H460 cells, and the patient survival analysis is correlative.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/metabo13050656

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    20E induces the expression of antioxidative stress response genes, including Gpx3, Gpx4, Gpx6, Gsr, Gss, Prdx1, Prdx5, Prdx6, Sod1, Sod2, Sod3, in H460 and H1299 cells.

    “The RT-PCR analysis revealed a number of differentially expressed genes associated with antioxidant response.”
    • Also stated in: § 3.1. 20E Down-Regulates ROS Levels and Induces the Expression of Antioxidative Response Genes · plain
      “Interestingly, depending on the cell line used, 20E induced the expression of different anti-oxidative genes to different levels (Figure 2): glutathione peroxidases (Gpx3, Gpx4, Gpx6), glutathion redustase (Gsr), glutathion syntetase (Gss), peroredoxines (Prdx1, Prdx5, Prdx6), superoxidismutases (Sod1, Sod2, Sod3), and others (Figure 2, Table S3).”
    Quote in the paperSubstantial claim
  • Findingown data

    After 24 h treatment, ROS levels were also suppressed by 20-25%.

    “As seen from Figure S1, after a day of treatment ROS levels were also suppressed by 20–25%.”
    Quote in the paperSubstantial claim
  • Findingown data

    20E only slightly suppressed (from 10 to 15%) the growth of all NSCLC cell lines.

    “The results demonstrated in Figure 3A–C and Table S2 imply that 20E only slightly suppressed (from 10 to 15%) the growth of all cell lines.”
    Quote in the paperSubstantial claim
  • Findingown data

    Cell cycle analysis showed no obvious changes with only 100 μM of 20E in decreased S-phase and increased G0/G1 in H1299 and A549 cells.

    “According to the cell cycle analysis, no obvious changes were observed with only 100 µM of 20E in the decreased S-phase and increased G0/G1 in H1299 and A549 cells (Figures S2–S4).”
    Quote in the paperNot a substantial claim
  • Findingown data

    RNA-seq analysis of H460 cells treated with 10 μM 20E for 24 h showed 619 down-regulated and 61 up-regulated genes.

    “All in all, we observed 619 down-regulated (Table S4) and 61 up-regulated (Table S5) genes.”
    Quote in the paperSubstantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 33

  • May combine two claims.

    Findingown data

    0.1 μM 20E suppressed total ROS by up to 20%, whereas other concentrations had inhibitory effects of up to 30-43% of the original level.

    “Thus, even 0.1 µM of 20E was able to suppress the total level of ROS by up to 20%, whereas other concentrations had inhibitory effects of up to 30–43% of the original level (Figure 1A–C, Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20E suppressed genes coding for ABC-transporters including ABCB6 and ABCC1, a cytokine TGF-β, MAPK signaling components, subunits of all respiratory chain complexes, and a number of amino acid importers.

    “It is also important to note that 20E suppressed genes which code for ABC-transporters, including those conferring multidrug resistance ABCB6 and ABCC1 (MRP1), a cytokine TGF-β, MAPK signaling components, subunits of all respiratory chain complexes, and a number of amino acid importers (Figure 4A,B, Table S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20E significantly suppressed both glycolysis and respiration intensities in all NSCLC cell lines.

    “We observed a significant 20E-mediated suppression of both glycolysis and respiration intensities in all cell lines (Figure 7, Figures S8 and S9, Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20E-mediated suppression of colony formation was observed in parallel with no obvious impact on cell cycle and apoptosis.

    “Moreover, we observed the 20E-mediated suppression of colony formation in parallel with no obvious impact on cell cycle and apoptosis (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The degree of 20E-mediated suppression of gene expression depends on the cell line; in most cases 20E in concentrations of 0.01 or 0.1 μM was sufficient to down-regulate the expression.

    “It should be noted that the degree of 20E-mediated suppression of gene expression depends on the cell line; however, in most cases 20E in concentrations of 0.01 or 0.1 µM was sufficient to down-regulate the expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Maximal respiration capacity and ATP production rate calculated based on SeaHorse data were both compromised by 20E.

    “The maximal respiration capacity and ATP production rate calculated based on SeaHorse data were also both compromised (Figure 7D,F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In A549 cells, 20E suppressed respiration and glycolysis by 30% and 25%, respectively.

    “For A549 cells, the values were 30% and 25%, respectively (Figure S9, Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20E displayed synergy with all compounds tested; CI values <1 reflect a significant synergistic interaction of 20E with 2-DG, MF, 3-BP, 5-FU, and gemcitabine.

    “The quantitative analysis of drug interaction showed that 20E displayed synergy with all of the compounds tested. The Combinational Index (CI) values (Table 1) and CI plots in Figure 8 and Figure S11 reflect a significant synergistic interaction (CI < 1) of 20E with 2-DG, MF, 3-BP, 5-FU, and gemcitabine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Western-blot results confirmed Real-time PCR data; 20E significantly suppressed HK2, LDHA, SHMT2, MTHFD2, c-Myc, and ATF4.

    “As seen from Figure 6, 20E significantly suppressed HK2, LDHA, SHMT2, MTHFD2, c-Myc, and ATF4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In H1299 cells, 1 μM 20E suppressed respiration and glycolysis by approximately 25% and 20%, respectively.

    “In H1299 cells, 20E in a concentration of 1 µM suppressed respiration and glycolysis by approximately 25% and 20%, respectively (Figure S8, Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    20E inhibited glycolysis, respiration, and ATP content.

    “In accordance with these data, 20E inhibited glycolysis, respiration, and ATP content.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20E inhibited the expression of key glycolytic genes HK2 and LDHA, genes coding for serine biosynthesis enzymes (PSAT1, PHGDH, PSPH), folate cycle enzymes (SHMT2, MTHFD2), and their transcriptional regulators c-Myc and ATF4.

    “Our further evaluation revealed that 20E inhibited the expression of key glycolytic genes HK2 and LDHA, as well as a number of genes coding for enzymes of serine biosynthesis (PSAT1, PHGDH, PSPH), folate cycle (SHMT2, MTHFD2), and their key transcriptional regulators—c-Myc and ATF4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    When 20E was used at 0.1 μM and higher, it had a clear impact on metabolism, sensitivity to metabolic inhibitors, and expression of CSC markers.

    “Importantly, when 20E was used at a concentration of 0.1 µM and higher, it had a clear impact on metabolism, sensitivity to metabolic inhibitors, and the expression of CSC markers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the paper's studies, 20E at a concentration of even 0.01 μM displayed a significant antioxidative effect and modulated the expression of metabolic genes.

    “In our studies, 20E in a concentration of even 0.01 µM displayed a significant antioxidative effect, and therefore modulated the expression of metabolic genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    20E displays multiple beneficial pharmacological properties in humans, including anabolic, adaptogenic, hypoglycemic, antioxidant, anti-inflammatory, hepato- and cardioprotective, antihypertensive, anti-fibrotic, and anti-COVID properties.

    “In humans, 20E has no hormonal activity but possesses a number of beneficial pharmacological properties including anabolic, adaptogenic, hypoglycemic, and antioxidant properties, as well as cardio-, hepato-, and neuroprotective features.”
    • Also stated in: § 1. Introduction · plain
      “20E displays anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, hepato- and cardioprotective, antioxidant, antihypertensive, anti-fibrotic, and anti-COVID properties, among others [1,2,3,4].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Dinan, L., Dioh, W., Veillet, S., and Lafont, R. (2021). 20-Hydroxyecdysone, from plant extracts to clinical use: Therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases. Biomedicines, 9. source

      Not checked in the free run.

    • cites [2] Chlebek, 2011, Ecdysterone and its activity on some degenerative diseases, Nat. Prod. Commun.

      Not checked in the free run.

    • cites [3] Latil, 2021, Developing new drugs that activate the protective arm of the renin–angiotensin system as a potential treatment for respiratory failure in COVID-19 patients, Drug Discov. Today source

      Not checked in the free run.

    • cites [4] Isenmann, 2019, Ecdysteroids as non-conventional anabolic agent: Performance enhancement by ecdysterone supplementation in humans, Arch. Toxicol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    20E and its derivatives sensitize breast cancer cells to genotoxic stress, induce autophagy, and attenuate multiple drug resistance.

    “We and others have shown that 20E and its derivates sensibilize breast cancer cells to genotoxic stress, induce autophagy, and attenuate multiple drug resistance [12,13,14,15,16,17,18,19].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [12] Shuvalov, 2020, An arthropod hormone, ecdysterone, inhibits the growth of breast cancer cells via different mechanisms, Front. Pharmacol. source

      Not checked in the free run.

    • cites [13] Martins, 2012, Significant activity of ecdysteroids on the resistance to doxorubicin in mammalian cancer cells expressing the human ABCB1 transporter, J. Med. Chem. source

      Not checked in the free run.

    • cites [14] Martins, 2015, Ecdysteroids sensitize MDR and non-MDR cancer cell lines to doxorubicin, paclitaxel, and vincristine but tend to protect them from cisplatin, BioMed Res. Int. source

      Not checked in the free run.

    • cites [15] Konovalova, 2002, Ecdysterone modulates antitumor activity of cytostatics and biosynthesis of macromolecules in tumor-bearing mice, Biol. Bull. Russ. Acad. Sci. source

      Not checked in the free run.

    • cites [16] Lisiak, 2021, Proapoptotic and proautophagic activity of 20-hydroxyecdysone in breast cancer cells in vitro, Chem.-Biol. Interact. source

      Not checked in the free run.

    • cites [17] Martins, 2018, Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam, Eur. J. Med. Chem. source

      Not checked in the free run.

    • cites [18] Bortolozzi, 2020, Ecdysteroid derivatives that reverse P-glycoprotein-mediated drug resistance, J. Nat. Prod. source

      Not checked in the free run.

    • cites [19] Savchenko, 2021, In vitro adjuvant antitumor activity of various classes of semi-synthetic poststerone derivatives, Bioorganic Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    20E displays low toxicity; the LD50 of 20E in mice is 9 g/kg of weight.

    “The LD50 of 20E in mice is 9 g/kg of weight [5]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Ogawa, S., Nishimoto, N., and Matsuda, H. (1974). Invertebrate Endocrinology and Hormonal Heterophylly, Springer.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clinical investigations have shown that 20E demonstrates a safe profile.

    “Clinical investigations have shown that this compound demonstrates a safe profile [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Dinan, L., Dioh, W., Veillet, S., and Lafont, R. (2021). 20-Hydroxyecdysone, from plant extracts to clinical use: Therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases. Biomedicines, 9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    20E possesses either direct ROS scavenging activity, or impacts ROS indirectly via affecting signaling pathways leading to a quick antioxidant response.

    “These data suggest that 20E possesses either direct ROS scavenging activity, or that it impacts ROS indirectly, via affecting the respective signaling pathways and thereby leading to a quick antioxidant response on the level of protein–protein interactions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metabolic rewiring, including different metabolic alterations, is considered to be one of the hallmarks of cancer.

    “Metabolic rewiring, including different metabolic alterations, is considered to be one of the “hallmarks of cancer” [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., and Barlev, N. (2021). Linking metabolic reprogramming, plasticity and tumor progression. Cancers, 13. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are ongoing efforts to utilize metabolic reprogramming in NSCLC as a therapeutic opportunity.

    “There are a lot of ongoing efforts to utilize the process of metabolic reprogramming in Non-Small Cell Lung Cancer (NSCLC) as a therapeutic opportunity [21,22,23,24].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [21] Mendes, C., and Serpa, J. (2019). Metabolic remodelling: An accomplice for new therapeutic strategies to fight lung cancer. Antioxidants, 8. source

      Not checked in the free run.

    • cites [22] Li, 2022, Tumor metabolic reprogramming in lung cancer progression, Oncol. Lett. source

      Not checked in the free run.

    • cites [23] Vanhove, 2019, The metabolic landscape of lung cancer: New insights in a disturbed glucose metabolism, Front. Oncol. source

      Not checked in the free run.

    • cites [24] Dowling, 2021, Shining a light on metabolic vulnerabilities in non-small cell lung cancer, Biochim. Et Biophys. Acta (BBA) Rev. Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several published reports have written about the ROS-scavenger and antioxidant properties of 20E in several in vitro and in vivo systems.

    “Several published reports have written about the ROS-scavenger and antioxidant properties of 20E in several in vitro [30,31] and in vivo systems [32,33].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [30] Kuzmenko, 2001, New functions of 20-hydroxyecdysone in lipid peroxidation, J. Oleo Sci. source

      Not checked in the free run.

    • cites [31] Cai, 2002, Antioxidative and free radical scavenging effects of ecdysteroids from Serratula strangulata, Can. J. Physiol. Pharmacol. source

      Not checked in the free run.

    • cites [32] Gholipour, 2022, Effects of the combination of high-intensity interval training and Ecdysterone on learning and memory abilities, antioxidant enzyme activities, and neuronal population in an Amyloid-beta-induced rat model of Alzheimer’s disease, Physiol. Behav. source

      Not checked in the free run.

    • cites [33] Yang, 2021, Ecdysterone attenuates the development of radiation-induced oral mucositis in rats at early stage, Radiat. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    H460, A549, and H1299 cell lines are frequently used as widely accepted cell models in the context of the metabolic rewiring of NSCLC.

    “H460, A549, and H1299 cell lines are frequently used as widely accepted cell models in the context of the metabolic rewiring of NSCLC [41,42,43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Parma, 2021, Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting, J. Exp. Clin. Cancer Res. source

      Not checked in the free run.

    • cites [42] Yu, 2022, Gankyrin modulated non-small cell lung cancer progression via glycolysis metabolism in a YAP1-dependent manner, Cell Death Discov. source

      Not checked in the free run.

    • cites [43] Zhang, 2020, FRK plays an oncogenic role in non-small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming, Int. J. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    According to the data, 20E may potentially affect glycolysis, oxidative phosphorylation, the metabolism of amino acids, and the biosynthesis of fatty acids and nucleotides.

    “According to the data obtained, 20E may potentially affect glycolysis, oxidative phosphorylation, the metabolism of amino acids, and the biosynthesis of fatty acids and nucleotides.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Cancer Stem Cells (CSCs) belong to a group of tumor cells with multidirectional differentiation capacity, high self-renewal potential, and tumorigenicity.

    “Cancer Stem Cells (CSCs) belong to a group of tumor cells with a multidirectional differentiation capacity, high self-renewal potential, and tumorigenicity [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Zheng, 2022, Lung cancer stem cell markers as therapeutic targets: An update on signaling pathways and therapies, Front. Oncol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Increased glycolysis and one-carbon metabolism are known to be widely observed in various malignancies.

    “As stated earlier, increased glycolysis and one-carbon metabolism are known to be widely observed in various malignancies [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., and Barlev, N. (2021). Linking metabolic reprogramming, plasticity and tumor progression. Cancers, 13. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A strong increase in ROS can induce damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death.

    “whereas a strong increase in ROS can induce the damage of proteins, nucleic acids, lipids, membranes, and organelles, which leads to cell death [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Nakamura, 2021, Reactive oxygen species in cancer: Current findings and future directions, Cancer Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    20E increased the activity of SOD, CAT, GPx, and GRx in neurons of an amyloid-beta-induced rat model of Alzheimer's disease.

    “Gholipour et al. [32], who demonstrated a 20E-mediated increase in the activity of superoxide dismutase (SOD), catalase (CAT), Glutathione Peroxidase (GPx), and Glutathione Reductase (GRx) in neurons of an amyloid-beta-induced rat model of Alzheimer’s disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Gholipour, 2022, Effects of the combination of high-intensity interval training and Ecdysterone on learning and memory abilities, antioxidant enzyme activities, and neuronal population in an Amyloid-beta-induced rat model of Alzheimer’s disease, Physiol. Behav. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    20E has previously been shown to possess antioxidant capacities in both in vitro systems and non-cancer cells.

    “As 20E has previously been shown to possess antioxidant capacities in both in vitro systems and non-cancer cells [30,31,32]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Kuzmenko, 2001, New functions of 20-hydroxyecdysone in lipid peroxidation, J. Oleo Sci. source

      Not checked in the free run.

    • cites [31] Cai, 2002, Antioxidative and free radical scavenging effects of ecdysteroids from Serratula strangulata, Can. J. Physiol. Pharmacol. source

      Not checked in the free run.

    • cites [32] Gholipour, 2022, Effects of the combination of high-intensity interval training and Ecdysterone on learning and memory abilities, antioxidant enzyme activities, and neuronal population in an Amyloid-beta-induced rat model of Alzheimer’s disease, Physiol. Behav. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    20E increased the amount of SOD in rat tongue after irradiation.

    “It was also reported that 20E increased the amount of SOD in rat tongue after irradiation [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Yang, 2021, Ecdysterone attenuates the development of radiation-induced oral mucositis in rats at early stage, Radiat. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS play a multifaceted, opposing role in cancer, favoring cancer onset at low doses and killing tumors at high doses.

    “ROS are known to play a multifaced, opposing role in cancer, by favoring cancer onset at low doses on the one hand, and killing tumors at high doses on the other hand [29,55].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Kirtonia, 2020, The multifaceted role of reactive oxygen species in tumorigenesis, Cell. Mol. Life Sci. source

      Not checked in the free run.

    • cites [55] Perillo, 2020, ROS in cancer therapy: The bright side of the moon, Exp. Mol. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A number of natural compounds with strong antioxidant properties (quercetin, kaempferol, rutin, resveratrol) have well-established anticancer activity and are widely studied as potential antineoplastic therapeutics.

    “A number of natural compounds with strong antioxidant properties (quercetin [59], kaempferol [60], rutin [61], resveratrol [62]) have a well-established anticancer activity and are widely studied as potential antineoplastic therapeutics [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Slika, 2022, Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms, Biomed. Pharmacother. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Different oncogenes and oncosuppressors have a critical impact on these metabolic pathways.

    “Different oncogenes and oncosupressors have a critical impact on these metabolic pathways [20,40,46,47,75,76].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [20] Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., and Barlev, N. (2021). Linking metabolic reprogramming, plasticity and tumor progression. Cancers, 13. source

      Not checked in the free run.

    • cites [40] Rosenzweig, 2018, Beyond the Warburg effect: How do cancer cells regulate one-carbon metabolism?, Front. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [46] Pan, 2021, Serine, glycine and one-carbon metabolism in cancer, Int. J. Oncol. source

      Not checked in the free run.

    • cites [47] Li, 2021, ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction, Cell Rep. source

      Not checked in the free run.

    • cites [75] Marbaniang, 2018, Dysregulation of glucose metabolism by oncogenes and tumor suppressors in cancer cells, Asian Pac. J. Cancer Prev. APJCP

      Not checked in the free run.

    • cites [76] Daks, 2021, p53-independent effects of Set7/9 lysine methyltransferase on metabolism of non-small cell lung cancer cells, Front. Oncol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Serine biosynthesis mediated by PSAT1, PHGDH, and PSPH opens the gates to one-carbon metabolism, and the folate cycle mediates redistribution of one-carbon groups to acceptors.

    “The serine biosynthesis mediated by three enzymes—PSAT1, PHGDH, and PSAT1—“opens the gates” to one-carbon metabolism, whereas its central part—the folate cycle—mediates the re-distribution of one-carbon groups to acceptors [46] (Figure 11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Pan, 2021, Serine, glycine and one-carbon metabolism in cancer, Int. J. Oncol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One-carbon metabolism supplies cancer cells with nucleotides, SAM, glutathione, some amino acids, etc.

    “One-carbon metabolism supplies cancer cells with nucleotides, which limit cell divisions: SAM—the main donor of methyl groups; glutathione—an important factor of redox homeostasis; some amino acids; etc. [40,65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Rosenzweig, 2018, Beyond the Warburg effect: How do cancer cells regulate one-carbon metabolism?, Front. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [65] Shuvalov, 2017, One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy, Oncotarget source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metabolic rewiring is considered one of the hallmarks of cancer.

    “Metabolic rewiring is considered one of the “hallmarks of cancer” [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., and Barlev, N. (2021). Linking metabolic reprogramming, plasticity and tumor progression. Cancers, 13. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Enhanced glycolysis implicates a myriad of molecular and functional processes to support cancer progression.

    “Enhanced glycolysis implicates a myriad of molecular and functional processes to support cancer progression [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] 2018, Molecular intricacies of aerobic glycolysis in cancer: Current insights into the classic metabolic phenotype, Crit. Rev. Biochem. Mol. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The up-regulation of glycolysis and one-carbon metabolism, and increased expression of corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.

    “The up-regulation of glycolysis and one-carbon metabolism, and the increased expression of genes coding for corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [66] Zhang, 2021, Overexpression of SHMT2 predicts a poor prognosis and promotes tumor cell growth in bladder cancer, Front. Genet. source

      Not checked in the free run.

    • cites [67] Zhang, 2023, Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer, Front. Oncol. source

      Not checked in the free run.

    • cites [68] Zhu, 2016, High Expression of PHGDH Predicts Poor Prognosis in Non–Small Cell Lung Cancer, Transl. Oncol. source

      Not checked in the free run.

    • cites [69] Huang, M.-Y., Liu, X.-Y., Shao, Q., Zhang, X., Miao, L., Wu, X.-Y., Xu, Y.-X., Wang, F., Wang, H.-Y., and Zeng, L. (2022). Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells. BMC Gastroenterol., 22. source

      Not checked in the free run.

    • cites [70] Mingtao, 2022, An integrated pan-cancer analysis of PSAT1: A potential biomarker for survival and immunotherapy, Front. Genet. source

      Not checked in the free run.

    • cites [71] Wang, 2021, High ATF4 expression is associated with poor prognosis, amino acid metabolism, and autophagy in gastric cancer, Front. Oncol. source

      Not checked in the free run.

    • cites [72] He, 2018, Association between c-Myc and colorectal cancer prognosis: A meta-analysis, Front. Physiol. source

      Not checked in the free run.

    • cites [73] Li, 2022, A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors, Sci. Rep. source

      Not checked in the free run.

    • cites [74] Yu, 2018, LDHA upregulation independently predicts poor survival in lung adenocarcinoma, but not in lung squamous cell carcinoma, Future Oncol. source

      Not checked in the free run.

    • Rests on an assumption: Increased glycolysis and one-carbon metabolism are two principal metabolic alterations in neoplasia.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    One-carbon metabolism links glycolysis with different biosynthetic processes.

    “Thus, it links glycolysis (the process of glucose assimilation) with different biosynthetic processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    20E is a non-toxic substance for which pharmacokinetic studies have been carried out in both rodents and humans.

    “20E is a non-toxic substance for which pharmacokinetic studies have been carried out in both rodents and humans [8,9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Wu, 2011, Research on relationship between tissue quantitative distribution of 3H-Achyranthes bidentata ecdysterone and channel-tropism of herbal drugs in mice, Zhongguo Zhong Yao Za Zhi=Zhongguo Zhongyao Zazhi=China J. Chin. Mater. Med.

      Not checked in the free run.

    • cites [9] Dinan, 2021, Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats, J. Steroid Biochem. Mol. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Molecular markers of CSCs are used for diagnosis and have therapeutic value because they are implicated in oncogenesis.

    “Molecular markers of CSCs are not only used for diagnosis, but also have a therapeutic value because they are implicated in oncogenesis [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Ayob, 2018, Cancer stem cells as key drivers of tumour progression, J. Biomed. Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    20E and its derivatives modulate the resistance of cancer cells to genotoxic drugs and mitigate multidrug resistance.

    “Furthermore, it has been shown previously that 20E and its derivates modulate the resistance of cancer cells to genotoxic drugs and mitigate multidrug resistance [12,13,14,15,16,17,18,19].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [12] Shuvalov, 2020, An arthropod hormone, ecdysterone, inhibits the growth of breast cancer cells via different mechanisms, Front. Pharmacol. source

      Not checked in the free run.

    • cites [13] Martins, 2012, Significant activity of ecdysteroids on the resistance to doxorubicin in mammalian cancer cells expressing the human ABCB1 transporter, J. Med. Chem. source

      Not checked in the free run.

    • cites [14] Martins, 2015, Ecdysteroids sensitize MDR and non-MDR cancer cell lines to doxorubicin, paclitaxel, and vincristine but tend to protect them from cisplatin, BioMed Res. Int. source

      Not checked in the free run.

    • cites [15] Konovalova, 2002, Ecdysterone modulates antitumor activity of cytostatics and biosynthesis of macromolecules in tumor-bearing mice, Biol. Bull. Russ. Acad. Sci. source

      Not checked in the free run.

    • cites [16] Lisiak, 2021, Proapoptotic and proautophagic activity of 20-hydroxyecdysone in breast cancer cells in vitro, Chem.-Biol. Interact. source

      Not checked in the free run.

    • cites [17] Martins, 2018, Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam, Eur. J. Med. Chem. source

      Not checked in the free run.

    • cites [18] Bortolozzi, 2020, Ecdysteroid derivatives that reverse P-glycoprotein-mediated drug resistance, J. Nat. Prod. source

      Not checked in the free run.

    • cites [19] Savchenko, 2021, In vitro adjuvant antitumor activity of various classes of semi-synthetic poststerone derivatives, Bioorganic Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A number of glycolytic and OxPHOS inhibitors are currently being investigated in preclinical and clinical studies.

    “A number of glycolytic and OxPHOS inhibitors are currently being investigated in preclinical and clinical studies [20,77].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., and Barlev, N. (2021). Linking metabolic reprogramming, plasticity and tumor progression. Cancers, 13. source

      Not checked in the free run.

    • cites [77] Sheng, 2016, Glycolysis inhibitors for anticancer therapy: A review of recent patents, Recent Pat. Anti-Cancer Drug Discov. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    2-DG, 3BP, and metformin sensitize cancer cells to different chemotherapeutic agents and irradiation.

    “2-DG, 3BP, and metformin sensitize cancer cells to different chemotherapeutic agents and irradiation [78,79].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Huang, Y., Sun, G., Sun, X., Li, F., Zhao, L., Zhong, R., and Peng, Y. (2020). The potential of lonidamine in combination with chemotherapy and physical therapy in cancer treatment. Cancers, 12. source

      Not checked in the free run.

    • cites [79] Fan, T., Sun, G., Sun, X., Zhao, L., Zhong, R., and Peng, Y. (2019). Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: Implications in tumor treatment. Cancers, 11. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhibition of energy and one-carbon metabolism in tumor cells usually sensitizes them to common therapeutics and radiotherapy.

    “In turn, the inhibition of the energy and one-carbon metabolism in tumor cells usually sensitizes them to common therapeutics and radiotherapy [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Liu, 2021, The mechanism of Warburg effect-induced chemoresistance in cancer, Front. Oncol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mitochondrial isoforms of folate cycle enzymes SHMT2 and MTHFD2 are very important targets for drug development in cancer therapy.

    “The mitochondrial isoforms of folate cycle enzymes serine hydroxymethyl transferase and methylene-tetrahydrofolate reductase (SHMT2 and MTHFD2) are very important targets for drug development in cancer therapy [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Cuthbertson, 2021, A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight, ACS Pharmacol. Transl. Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism.

    “Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism [44,45,46,49].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [44] Goetzman, 2018, The role for Myc in coordinating glycolysis, oxidative phosphorylation, glutaminolysis, and fatty acid metabolism in normal and neoplastic tissues, Front. Endocrinol. source

      Not checked in the free run.

    • cites [45] Cargill, 2021, Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer, Cancer Metab. source

      Not checked in the free run.

    • cites [46] Pan, 2021, Serine, glycine and one-carbon metabolism in cancer, Int. J. Oncol. source

      Not checked in the free run.

    • cites [49] Sorge, 2020, ATF4-induced warburg metabolism drives over-proliferation in Drosophila, Cell Rep. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CSCs are a subpopulation of tumor cells with capacity for sustained self-renewal that can drive tumor initiation, relapses, metastasis, and resistance to therapy.

    “CSCs are a subpopulation of tumor cells with the capacity for sustained self-renewal that, in turn, can not only drive tumor initiation but can also cause relapses, metastasis, and resistance to therapy [82,83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Walcher, 2020, Cancer stem cells—Origins and biomarkers: Perspectives for targeted personalized therapies, Front. Immunol. source

      Not checked in the free run.

    • cites [83] Chang, 2016, Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance, Medicine source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In muscle cells, 20E interacts with both MAS1 and estrogen receptor (ER), which both affect 20E-modulated protein synthesis and myostatin expression.

    “For example, it is already established that in muscle cells, 20E interacts with both MAS1 and estrogen receptor (ER), which both affect the 20E-modulated protein synthesis and myostatin expression [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Lafont, 2022, 20-Hydroxyecdysone activates the protective arm of the RAAS via the MAS receptor, J. Mol. Endocrinol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    According to literature, 20E possesses anti-oxidant, hepato- and cardioprotective, anti-inflammatory, hypolipidemic, hypoglycemic, and other pharmacological activities.

    “According to the literature published to date, 20E possesses anti-oxidant, hepato- and cardioprotective, anti-inflammatory, hypolipidemic, hypoglycemic, and other pharmacological activities [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Dinan, L., Dioh, W., Veillet, S., and Lafont, R. (2021). 20-Hydroxyecdysone, from plant extracts to clinical use: Therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases. Biomedicines, 9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    20E has been evaluated in clinical trials to treat several disorders, including severe consequences of COVID-19 (NCT04472728).

    “It has been evaluated in clinical trials to treat several disorders, including the severe consequences of COVID-19 (NCT04472728).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT04472728

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Low 20E concentration enhanced the growth of insect cells and protein synthesis in mice myotubes, whereas high concentration inhibited these processes.

    “For instance, it was reported that low 20E concentration enhanced the growth of insect cells [88] and protein synthesis in mice myotubes [89], whereas a high concentration inhibited these processes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] Kurtti, 1983, The effects of 20-hydroxyecdysone and juvenile hormone III on tick cells, J. Parasitol. source

      Not checked in the free run.

    • cites [89] Lafont, R., Raynal, S., Serova, M., Didry-Barca, B., Guibout, L., Latil, M., Dilda, P.J., Dioh, W., and Veillet, S. (2020). 20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor. BioRxiv. source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    Targeting both glycolysis and respiration can be an effective strategy to eliminate CSCs.

    “As the targeting of both glycolysis and respiration can be an effective strategy to eliminate CSCs, the 20E-induced down-regulation of these processes may theoretically suppress the CSCs’ population.”

  • The paper relies on this without support.

    Spheroid culture creates more physiological conditions which favor CSCs.

    “Secondly, to create more physiological conditions which favor CSCs, we established the growth of spheroids using ultra-low adhesion 10 cm cell culture dishes.”

  • The paper relies on this without support.

    CSCs represent a very important challenge for antineoplastic therapy.

    “As CSCs represent a very important challenge for antineoplastic therapy”

  • The paper relies on this without support.

    Increased glycolysis and one-carbon metabolism are two principal metabolic alterations in neoplasia.

    “Increased glycolysis and one-carbon metabolism are two principal metabolic alterations in neoplasia.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ATP assay treatment duration differs between Methods and Results

    Major

    The Methods specify 48 hours of 20E treatment before the ATP assay, whereas the Results say the cells were treated for three days.

  • Serine-biosynthesis enzyme list repeats PSAT1 in place of PSPH

    Minor

    The Discussion names PSAT1 twice in its list of three serine-biosynthesis enzymes, whereas the Results identify the three as PSAT1, PSPH, and PHGDH.

  • ATP assay kit supplier differs between Methods and Results

    Minor

    The Methods identify the ATP assay kit as an AbCam product, while the Results identify it as a Sigma product.

  • Spheroid treatment doses differ between Methods and Results

    Minor

    The Results say spheroid cultures received the same doses as the preceding experiment (0.1-100 μM), but the Methods specify only 1 μM for spheroids.

4 of 4

Cites

1 retracted

Flagged first, then by citations

3 of the 91 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Ogawa, S., Nishimoto, N., and Matsuda, H. (1974). Invertebrate Endocrinology and Hormonal Heterophylly, Springer.

Cited by

Sorted by citations

Related

Authors
Shuvalov, O., Kirdeeva, Y., Fefilova, E., Netsvetay, S., Zorin, M., Vlasova, Y., Fedorova, O., Daks, A., Parfenyev, S., & Barlev, N.
Affiliations
  • Russian Academy of Sciences (RU)
  • Federal Almazov North-West Medical Research Centre (RU)
Corresponding author
  • Shuvalov, Oleg
  • Barlev, Nickolai
ORCID
Venue
Metabolites
Publisher
MDPI AG
Published
2023-05-15
Volume
13
Issue
5
Pages
656
ISSN
2218-1989 (ISSN-L)
DOI
10.3390/metabo13050656
PMC
PMC10223942
OpenAlex
W4376611238
Semantic Scholar
5273c43adcbe1b061cb48284cc1bd8db67f9edd8
Cited by
21
References
91
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 4
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Metabolites (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Nazarbayev University Repository (Nazarbayev University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Recruitment of the Leading Scientists into the Russian Institutions of Higher Education (075-15-2021-600)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords
20-hydroxyecdysone, non-small cell lung cancer, antioxidant activity, anticancer activity, oxidative stress response genes, glycolysis inhibition, one-carbon metabolism, c-Myc, ATF4, cancer stem cells, metabolic reprogramming, respiration inhibition, metabolic inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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