Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma

Our plain-English summary of Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma, by M.A. Franczak, O. Krol, G. Harasim, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: M.A. Franczak, O. Krol, G. Harasim, A. Jedrzejewska, N. Zaffaroni, C. Granchi, F. Minutolo, A. Avan, E. Giovannetti, R.T. Smolenski, G.J. Peters
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(9)
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD+ metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells. Effects on energy metabolism were measured by both analysis of nucleotides using RP-HPLC and evaluation of glycolysis and respiration parameters using a Seahorse Analyzer system. All compounds reduced the growth of MM cells in the µmolar range. Interestingly, in H2052 cells, PGL14 decreased ATP concentration from 37 to 23 and NAD+ from 6.5 to 2.3 nmol/mg protein. NHI-2 reduced the ATP/ADP ratio by 76%. The metabolic effects of the inhibitors were stronger in pleural MM and in combination, while in HMEC-1 ATP reduction was 10% lower compared to that of the H2052 cells, and we observed a minor influence on mitochondrial respiration. To conclude, both inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD+, and were synergistic in the cells with the highest metabolic modulation. This underlines cellular energy metabolism as a potential target for combined treatments in selected cases of MM.

In plain English

This was a laboratory study of cells grown in dishes. No patients were studied, and asbestos exposure was not examined. The authors tested two experimental blockers of the glucose transporter GLUT-1 (PGL13, PGL14) and two of the enzyme LDH-A (NHI-1, NHI-2). They used peritoneal mesothelioma cells (MESO-II, STO), pleural mesothelioma cells (NCI-H2052, NCI-H28) and non-cancerous cells (HMEC-1). All compounds reduced mesothelioma cell growth at micromolar concentrations. For PGL14, the concentration that halved growth was 6.4 micromolar in MESO-II cells and 44.4 in H2052 cells. PGL14 and NHI-2 together had strong synergistic effects in H2052 cells and additive or synergistic effects in MESO-II cells. The GLUT-1 inhibitors lowered the energy molecules ATP and NAD+ in every cell line except MESO-II. NHI-2 lowered nucleotides in H28, H2052 and MESO-II cells, and NHI-1 did so significantly only in H2052 cells. In H2052 cells, PGL14 lowered ATP from 37 to 23 nmol per mg protein. Nucleotide levels in the non-cancerous cells fell only slightly. The effect on mitochondrial respiration was minor. The authors concluded that their findings support further investigation of these compounds as a potential treatment strategy for mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) cell-culture experiment
• Who was studied: Human cell lines: peritoneal mesothelioma cells MESO-II and STO (derived from patients' surgical samples, Milan, Italy), pleural mesothelioma cell lines NCI-H2052 and NCI-H28, and non-cancerous human dermal microvascular endothelial cells HMEC-1 (the last three obtained from ATCC)
• Exposure: No asbestos exposure was studied. Cells were treated with experimental GLUT-1 inhibitors (PGL13, PGL14) and LDH-A inhibitors (NHI-1, NHI-2), alone and in combination. Growth tests used concentrations of 0.01 to 60 micromolar for 72 hours. Metabolism tests used each compound's 50% growth-inhibitory concentration for 24 hours.
• Main results:
  • The LDH-A inhibitors halved mesothelioma cell growth at about 20 to 25 micromolar. For NHI-2, H2052 cells had the highest value (43.5 plus or minus 4.8 micromolar) and MESO-II cells the lowest (18.5 plus or minus 2.0 micromolar).
  • The GLUT-1 inhibitor PGL14 halved growth at 6.4 micromolar in MESO-II cells and 44.4 micromolar in H2052 cells. For PGL13 the values ranged from 13 to 39 micromolar.
  • Combining NHI-2 and PGL14 gave strong synergistic effects in H2052 cells and additive or synergistic effects in MESO-II cells.
  • The GLUT-1 inhibitors lowered ATP and NAD+ in all cell lines except MESO-II, and PGL14 was most effective in H2052 cells.
  • NHI-2 lowered nucleotide levels in H28, H2052 and MESO-II cells. NHI-1 significantly reduced nucleotide pools only in H2052 cells.
  • The article's abstract reports that in H2052 cells, PGL14 lowered ATP from 37 to 23 nmol per mg protein and NAD+ from 6.5 to 2.3 nmol per mg protein.
  • The ATP/ADP energy ratio fell in most cell lines, most clearly in H2052 cells for all inhibitors. The NADH/NAD+ ratio rose in H28, H2052 and STO cells but not in MESO-II cells.
  • In the non-cancerous HMEC-1 cells, nucleotide levels fell only slightly. The ATP/ADP and NADH/NAD+ ratios changed significantly only with 45 micromolar NHI-2.
  • In MESO-II cells, the combined inhibitors lowered all nucleotides, and PGL14 with NHI-2 had the largest effect.
  • In H2052 cells, the combination only slightly reduced mitochondrial function, but it significantly reduced ATP production by the mitochondria.
• The authors' conclusion: The authors concluded that the GLUT-1 and LDH-A inhibitors were cytotoxic against mesothelioma cells and synergistic in combination. They reported a minor influence on mitochondrial respiration and only slight changes in non-cancer cells. They said their findings support further investigation of these compounds as a potential new therapeutic strategy for mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lactate Dehydrogenase (LDH), Mesothelioma.

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