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Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI
SIMPLE SUMMARY: Dysregulated metabolism is a key hallmark of cancer cells and many solid tumors are acidic. Acidosis is responsible for cancer aggressiveness and for resistance to several treatments. In the present study, we evaluated to which extent tumor acidosis was influenced upon inhibition of...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428345/ https://www.ncbi.nlm.nih.gov/pubmed/34503089 http://dx.doi.org/10.3390/cancers13174278 |
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author | Buyse, Chloé Joudiou, Nicolas Corbet, Cyril Feron, Olivier Mignion, Lionel Flament, Julien Gallez, Bernard |
author_facet | Buyse, Chloé Joudiou, Nicolas Corbet, Cyril Feron, Olivier Mignion, Lionel Flament, Julien Gallez, Bernard |
author_sort | Buyse, Chloé |
collection | PubMed |
description | SIMPLE SUMMARY: Dysregulated metabolism is a key hallmark of cancer cells and many solid tumors are acidic. Acidosis is responsible for cancer aggressiveness and for resistance to several treatments. In the present study, we evaluated to which extent tumor acidosis was influenced upon inhibition of the import of pyruvate into the mitochondria, the powerhouse of the cell. Using advanced molecular imaging to measure non-invasively the acidity in a model of breast cancer, we found that while some tumor regions became much more acidic, others did not show any change. This study highlights the capacity of this advanced technology to reveal the heterogeneity of response to the treatment. ABSTRACT: (1) Background: The acidosis of the tumor micro-environment may have profound impact on cancer progression and on the efficacy of treatments. In the present study, we evaluated the impact of a treatment with UK-5099, a mitochondrial pyruvate carrier (MPC) inhibitor on tumor extracellular pH (pHe); (2) Methods: glucose consumption, lactate secretion and extracellular acidification rate (ECAR) were measured in vitro after exposure of cervix cancer SiHa cells and breast cancer 4T1 cells to UK-5099 (10 µM). Mice bearing the 4T1 tumor model were treated daily during four days with UK-5099 (3 mg/kg). The pHe was evaluated in vivo using either chemical exchange saturation transfer (CEST)-MRI with iopamidol as pHe reporter probe or (31)P-NMR spectroscopy with 3-aminopropylphosphonate (3-APP). MR protocols were applied before and after 4 days of treatment; (3) Results: glucose consumption, lactate release and ECAR were increased in both cell lines after UK-5099 exposure. CEST-MRI showed a significant decrease in tumor pHe of 0.22 units in UK-5099-treated mice while there was no change over time for mice treated with the vehicle. Parametric images showed a large heterogeneity in response with 16% of voxels shifting to pHe values under 7.0. In contrast, (31)P-NMR spectroscopy was unable to detect any significant variation in pHe; (4) Conclusions: MPC inhibition led to a moderate acidification of the extracellular medium in vivo. CEST-MRI provided high resolution parametric images (0.44 µL/voxel) of pHe highlighting the heterogeneity of response within the tumor when exposed to UK-5099. |
format | Online Article Text |
id | pubmed-8428345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84283452021-09-10 Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI Buyse, Chloé Joudiou, Nicolas Corbet, Cyril Feron, Olivier Mignion, Lionel Flament, Julien Gallez, Bernard Cancers (Basel) Article SIMPLE SUMMARY: Dysregulated metabolism is a key hallmark of cancer cells and many solid tumors are acidic. Acidosis is responsible for cancer aggressiveness and for resistance to several treatments. In the present study, we evaluated to which extent tumor acidosis was influenced upon inhibition of the import of pyruvate into the mitochondria, the powerhouse of the cell. Using advanced molecular imaging to measure non-invasively the acidity in a model of breast cancer, we found that while some tumor regions became much more acidic, others did not show any change. This study highlights the capacity of this advanced technology to reveal the heterogeneity of response to the treatment. ABSTRACT: (1) Background: The acidosis of the tumor micro-environment may have profound impact on cancer progression and on the efficacy of treatments. In the present study, we evaluated the impact of a treatment with UK-5099, a mitochondrial pyruvate carrier (MPC) inhibitor on tumor extracellular pH (pHe); (2) Methods: glucose consumption, lactate secretion and extracellular acidification rate (ECAR) were measured in vitro after exposure of cervix cancer SiHa cells and breast cancer 4T1 cells to UK-5099 (10 µM). Mice bearing the 4T1 tumor model were treated daily during four days with UK-5099 (3 mg/kg). The pHe was evaluated in vivo using either chemical exchange saturation transfer (CEST)-MRI with iopamidol as pHe reporter probe or (31)P-NMR spectroscopy with 3-aminopropylphosphonate (3-APP). MR protocols were applied before and after 4 days of treatment; (3) Results: glucose consumption, lactate release and ECAR were increased in both cell lines after UK-5099 exposure. CEST-MRI showed a significant decrease in tumor pHe of 0.22 units in UK-5099-treated mice while there was no change over time for mice treated with the vehicle. Parametric images showed a large heterogeneity in response with 16% of voxels shifting to pHe values under 7.0. In contrast, (31)P-NMR spectroscopy was unable to detect any significant variation in pHe; (4) Conclusions: MPC inhibition led to a moderate acidification of the extracellular medium in vivo. CEST-MRI provided high resolution parametric images (0.44 µL/voxel) of pHe highlighting the heterogeneity of response within the tumor when exposed to UK-5099. MDPI 2021-08-25 /pmc/articles/PMC8428345/ /pubmed/34503089 http://dx.doi.org/10.3390/cancers13174278 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Buyse, Chloé Joudiou, Nicolas Corbet, Cyril Feron, Olivier Mignion, Lionel Flament, Julien Gallez, Bernard Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title | Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title_full | Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title_fullStr | Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title_full_unstemmed | Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title_short | Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI |
title_sort | impact of inhibition of the mitochondrial pyruvate carrier on the tumor extracellular ph as measured by cest-mri |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428345/ https://www.ncbi.nlm.nih.gov/pubmed/34503089 http://dx.doi.org/10.3390/cancers13174278 |
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