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Article

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

by
Marika A. Franczak
1,2,
Oliwia Krol
1,
Gabriela Harasim
1,
Agata Jedrzejewska
1,
Nadia Zaffaroni
3,
Carlotta Granchi
4,
Filippo Minutolo
4,
Amir Avan
2,5,6,
Elisa Giovannetti
2,7,*,
Ryszard T. Smolenski
1 and
Godefridus J. Peters
1,2,*
1
Department of Biochemistry, Medical University of Gdansk, 80-210 Gdańsk, Poland
2
Department of Medical Oncology, Amsterdam University Medical Centers, Location VUmc, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
3
Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy
4
Dipartimento di Farmacia, Università di Pisa, 56126 Pisa, Italy
5
Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad 91886-17871, Iran
6
Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad 91886-17871, Iran
7
Fondazione Pisana per la Scienza, 56124 Pisa, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(9), 7771; https://doi.org/10.3390/ijms24097771
Submission received: 29 March 2023 / Revised: 18 April 2023 / Accepted: 19 April 2023 / Published: 24 April 2023
(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)
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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.
Keywords: malignant mesothelioma; lactate dehydrogenase; glucose transporter type 1; chemoresistance; anticancer treatment; cancer metabolism malignant mesothelioma; lactate dehydrogenase; glucose transporter type 1; chemoresistance; anticancer treatment; cancer metabolism

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MDPI and ACS Style

Franczak, M.A.; Krol, O.; Harasim, G.; Jedrzejewska, A.; Zaffaroni, N.; Granchi, C.; Minutolo, F.; Avan, A.; Giovannetti, E.; Smolenski, R.T.; et al. Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma. Int. J. Mol. Sci. 2023, 24, 7771. https://doi.org/10.3390/ijms24097771

AMA Style

Franczak MA, Krol O, Harasim G, Jedrzejewska A, Zaffaroni N, Granchi C, Minutolo F, Avan A, Giovannetti E, Smolenski RT, et al. Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma. International Journal of Molecular Sciences. 2023; 24(9):7771. https://doi.org/10.3390/ijms24097771

Chicago/Turabian Style

Franczak, Marika A., Oliwia Krol, Gabriela Harasim, Agata Jedrzejewska, Nadia Zaffaroni, Carlotta Granchi, Filippo Minutolo, Amir Avan, Elisa Giovannetti, Ryszard T. Smolenski, and et al. 2023. "Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma" International Journal of Molecular Sciences 24, no. 9: 7771. https://doi.org/10.3390/ijms24097771

APA Style

Franczak, M. A., Krol, O., Harasim, G., Jedrzejewska, A., Zaffaroni, N., Granchi, C., Minutolo, F., Avan, A., Giovannetti, E., Smolenski, R. T., & Peters, G. J. (2023). Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma. International Journal of Molecular Sciences, 24(9), 7771. https://doi.org/10.3390/ijms24097771

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