bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2020‒11‒08
six papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Antitumor Therapy under Hypoxic Microenvironment by the Combination of 2-Methoxyestradiol and Sodium Dichloroacetate on Human Non-Small-Cell Lung Cancer.
  2. A Novel Lipofuscin-detecting Marker of Senescence Relates With Hypoxia, Dysregulated Autophagy and With Poor Prognosis in Non-small-cell-lung Cancer.
  3. Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC.
  4. Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients.
  5. Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC.
  6. Metabolic syndrome and the incidence of lung cancer: a meta-analysis of cohort studies.
  1. Oxid Med Cell Longev. 2020 ;2020 3176375
    Antitumor Therapy under Hypoxic Microenvironment by the Combination of 2-Methoxyestradiol and Sodium Dichloroacetate on Human Non-Small-Cell Lung Cancer.
    Romero Y, Castillejos-López M, Romero-García S, Aguayo AS, Herrera I, Garcia-Martin MO, Torres-Espíndola LM, Negrete-García MC, Olvera AC, Huerta-Cruz JC, Cruz RV, Cisneros J, Soto EF, Solís-Chagoyán H, Mendoza-Milla C, Cabello-Gutiérrez C, Ruiz V, Aquino-Gálvez A.
      A hypoxic microenvironment is a hallmark in different types of tumors; this phenomenon participates in a metabolic alteration that confers resistance to treatments. Because of this, it was proposed that a combination of 2-methoxyestradiol (2-ME) and sodium dichloroacetate (DCA) could reduce this alteration, preventing proliferation through the reactivation of aerobic metabolism in lung adenocarcinoma cell line (A549). A549 cells were cultured in a hypoxic chamber at 1% O2 for 72 hours to determine the effect of this combination on growth, migration, and expression of hypoxia-inducible factors (HIFs) by immunofluorescence. The effect in the metabolism was evaluated by the determination of glucose/glutamine consumption and the lactate/glutamate production. The treatment of 2-ME (10 μM) in combination with DCA (40 mM) under hypoxic conditions showed an inhibitory effect on growth and migration. Notably, this reduction could be attributed to 2-ME, while DCA had a predominant effect on metabolic activity. Moreover, this combination decreases the signaling of HIF-3α and partially HIF-1α but not HIF-2α. The results of this study highlight the antitumor activity of the combination of 2-ME 10 μl/DCA 40 mM, even in hypoxic conditions.
    DOI:  https://doi.org/10.1155/2020/3176375
  2. In Vivo. 2020 Nov-Dec;34(6):34(6): 3187-3193
    A Novel Lipofuscin-detecting Marker of Senescence Relates With Hypoxia, Dysregulated Autophagy and With Poor Prognosis in Non-small-cell-lung Cancer.
    Giatromanolaki A, Kouroupi M, Balaska K, Koukourakis MI.
      BACKGROUND/AIM: The role of senescence in defining tumor aggressiveness at a clinical level remains obscure. A novel mixed histochemical/immunohistochemical method (SenTraGor™, STG) detecting lipofuscin accumulation allows the assessment of senescent cells in paraffin-embedded tissue material.MATERIALS AND METHODS: STG expression was quantified in 98 surgically resected primary non-small-cell-lung carcinomas (NSCLC). Data were analyzed in parallel with other immunohistochemical markers related to hypoxia and autophagy.
    RESULTS: Strong STG staining was noted in 36/98 cases (36.7%). High STG expression was significantly associated with high HIF1α expression and high expression of glucose (GLUT1) and monocarboxylate (MCT2) transporters, pointing to a link between senescence, hypoxia and glycolysis. High STG expression was also linked with high cytoplasmic accumulation of MAP1-LC3B, TFEB and LAMP2a, suggestive of a blockage of autophagy flux in tumors with intense senescence. Survival analysis showed a direct association with poor survival, independently of stage.
    CONCLUSION: SenTraGor™ provides a reliable methodology to detect lipofuscin accumulation in cancer cells in paraffin-embedded tissues, opening a new field for translational studies focused on senescence.
    Keywords:  Senescence; autophagy; glycolysis; hypoxia; lipofuscin; lung cancer
    DOI:  https://doi.org/10.21873/invivo.12154
  3. Transl Oncol. 2020 Oct 30. pii: S1936-5233(20)30412-5. [Epub ahead of print]14(1): 100920
    Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC.
    Xia M, Li X, Diao Y, Du B, Li Y.
      Regulated by the tumor microenvironment, the metabolic network of the tumor is reprogrammed, driven by oncogenes and tumor suppressor genes. The metabolic phenotype of tumors of different driven-genes and different tissue types is extremely heterogeneous. KRAS-mutant non-small cell lung cancer (NSCLC) has glutamine dependence. In this study, we demonstrated that glutamine utilization of KRAS-mutant NSCLC was higher than that of KRAS wild-type. CB839, an efficient glutaminase inhibitor, synergized with the MEK inhibitor selumetinib to enhance antitumor activity in KRAS-mutant NSCLC cells and xenografts, and the therapeutic response could be well identified by 18F-FDG PET imaging. Combination therapy induced redox stress, manifesting as a decrease in mitochondrial membrane potential and an increase in ROS levels, and energetic stress manifesting as suppression of glycolysis and glutamine degradation. The phosphorylation of AKT was also suppressed. These effects combined to induce autophagy and thereby caused cancer cell death. Our results suggest that dual inhibition of the MEK-ERK pathway and glutamine metabolism activated by KRAS mutation may be an effective treatment strategy for KRAS-driven NSCLC.
    Keywords:  Autophagy; Glutaminase; KRAS; Microenvironment
    DOI:  https://doi.org/10.1016/j.tranon.2020.100920
  4. J Pers Med. 2020 Nov 04. pii: E208. [Epub ahead of print]10(4):
    Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients.
    Zizzari IG, Filippo AD, Scirocchi F, Di Pietro FR, Rahimi H, Ugolini A, Scagnoli S, Vernocchi P, Del Chierico F, Putignani L, Rughetti A, Marchetti P, Nuti M, Botticelli A, Napoletano C.
      Patients with non-small cell lung cancer (NSCLC) have been shown to benefit from the introduction of anti-PD1 treatment. However, not all patients experience tumor regression and durable response. The identification of a string of markers that are direct or indirect indicators of the immune system fitness is needed to choose optimal therapeutic schedules in the management of NSCLC patients. We analyzed 34 immuno-related molecules (14 soluble immune checkpoints, 17 cytokines/chemokines, 3 adhesion molecules) released in the serum of 22 NSCLC patients under Nivolumab treatment and the gut metabolomic profile at baseline. These parameters were correlated with performance status (PS) and/or response to treatment. Nivolumab affected the release of soluble immune checkpoints (sICs). Patients with a better clinical outcome and with an optimal PS (PS = 0) showed a decreased level of PD1 and maintained low levels of several sICs at first clinical evaluation. Low levels of PDL1, PDL2, Tim3, CD137 and BTLA4 were also correlated with a long response to treatment. Moreover, responding patients showed a high proportion of eubiosis-associated gut metabolites. In this exploratory study, we propose a combination of immunological and clinical parameters (sICs, PS and gut metabolites) for the identification of patients more suitable for Nivolumab treatment. This string of parameters validated in a network analysis on a larger cohort of patients could help oncologists to improve their decision-making in an NSCLC setting.
    Keywords:  biomarkers; gut metabolites; immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; soluble immune checkpoints
    DOI:  https://doi.org/10.3390/jpm10040208
  5. J Adv Res. 2020 Nov;26 95-110
    Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC.
    Li XY, Wang DP, Lu GQ, Liu KL, Zhang TJ, Li S, Mohamed O K, Xue WH, Qian XH, Meng FH.
      Introduction: The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment.Objectives: Our research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC).
    Methods: We obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound's effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model.
    Results: A series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX.
    Conclusion: The anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC.
    DOI:  https://doi.org/10.1016/j.jare.2020.07.008
  6. Diabetol Metab Syndr. 2020 ;12 95
    Metabolic syndrome and the incidence of lung cancer: a meta-analysis of cohort studies.
    Qiao L, Ma D, Lv H, Shi D, Fei M, Chen Y, Xie F, Wang Z, Wang Y, Liang W, Hu P.
      Background: Metabolic syndrome (MetS) has been related to the pathogenesis of variety categories of cancers. This meta-analysis aimed to determine the association between MetS and the incidence of lung cancer.Methods: Relevant cohort studies were identified by search of PubMed, Embase, and Cochrane's Library databases. Cochrane's Q test and I2 statistic were used to analyze the heterogeneity. Random-effect model which incorporates the potential heterogeneity was used for the meta-analysis.
    Results: Five cohort studies with 188,970 participants were included. A total of 1,295 lung cancer cases occurred during follow-up. Meta-analyses showed that neither MetS defined by the revised NCEP-ATP III criteria (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.84 to 1.05, p = 0.25; I2 = 0) nor the IDF criteria (HR: 0.82, 95% CI: 0.61 to 1.11, p = 0.20; I2 = 0) was associated with an affected risk of lung cancer. Subgroup analyses showed consistent results in women and in men, in studies performed in Asian and non-Asian countries, and in prospective and retrospective cohorts (p all > 0.05). Meta-analysis limited to studies with the adjustment of smoking status also showed similar results (HR: 0.91, 95% CI: 0.80 to 1.05, p = 0.21; I2 = 0). No publication bias was detected based on the Egger regression test (p = 0.32).
    Conclusions: Current evidence from cohort studies does not support that MetS is an independent risk factor for the incidence of lung cancer.
    Keywords:  Cohort study; Lung cancer; Meta-analysis; Metabolic syndrome
    DOI:  https://doi.org/10.1186/s13098-020-00598-0
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