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Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin

Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deac...

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Autores principales: Granit, Avital, Mishra, Kumudesh, Barasch, Dinorah, Peretz-Yablonsky, Tamar, Eyal, Sara, Kakhlon, Or
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760697/
https://www.ncbi.nlm.nih.gov/pubmed/36544904
http://dx.doi.org/10.3389/fcell.2022.1014798
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author Granit, Avital
Mishra, Kumudesh
Barasch, Dinorah
Peretz-Yablonsky, Tamar
Eyal, Sara
Kakhlon, Or
author_facet Granit, Avital
Mishra, Kumudesh
Barasch, Dinorah
Peretz-Yablonsky, Tamar
Eyal, Sara
Kakhlon, Or
author_sort Granit, Avital
collection PubMed
description Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deacetylase inhibitor (HDACi) valproic acid (VPA) can counter the cisplatin-induced metabolic changes leading to its resistance. We performed targeted metabolomic and real time PCR analyses on MDA-MB-231 TNBC cells treated with cisplatin, VPA or their combination. 22 (88%) out of the 25 metabolites most significantly modified by the treatments, were acylcarnitines (AC) and three (12%) were phosphatidylcholines (PCs). The most discernible effects were up-modulation of AC by cisplatin and, contrarily, their down-modulation by VPA, which was partial in the VPA-cisplatin combination. Furthermore, the VPA-cisplatin combination increased PCs, sphingomyelins (SM) and hexose levels, as compared to the other treatments. These changes predicted modulation of different metabolic pathways, notably fatty acid degradation, by VPA. Lastly, we also show that the VPA-cisplatin combination increased mRNA levels of the fatty acid oxidation (FAO) promoting enzymes acyl-CoA synthetase long chain family member 1 (ACSL1) and decreased mRNA levels of fatty acid synthase (FASN), which is the rate limiting enzyme of long-chain fatty acid synthesis. In conclusion, VPA supplementation altered lipid metabolism, especially fatty acid oxidation and lipid synthesis, in cisplatin-treated MDA-MB-231 TNBC cells. This metabolic reprogramming might reduce cisplatin resistance. This finding may lead to the discovery of new therapeutic targets, which might reduce side effects and counter drug tolerance in TNBC patients.
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spelling pubmed-97606972022-12-20 Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin Granit, Avital Mishra, Kumudesh Barasch, Dinorah Peretz-Yablonsky, Tamar Eyal, Sara Kakhlon, Or Front Cell Dev Biol Cell and Developmental Biology Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deacetylase inhibitor (HDACi) valproic acid (VPA) can counter the cisplatin-induced metabolic changes leading to its resistance. We performed targeted metabolomic and real time PCR analyses on MDA-MB-231 TNBC cells treated with cisplatin, VPA or their combination. 22 (88%) out of the 25 metabolites most significantly modified by the treatments, were acylcarnitines (AC) and three (12%) were phosphatidylcholines (PCs). The most discernible effects were up-modulation of AC by cisplatin and, contrarily, their down-modulation by VPA, which was partial in the VPA-cisplatin combination. Furthermore, the VPA-cisplatin combination increased PCs, sphingomyelins (SM) and hexose levels, as compared to the other treatments. These changes predicted modulation of different metabolic pathways, notably fatty acid degradation, by VPA. Lastly, we also show that the VPA-cisplatin combination increased mRNA levels of the fatty acid oxidation (FAO) promoting enzymes acyl-CoA synthetase long chain family member 1 (ACSL1) and decreased mRNA levels of fatty acid synthase (FASN), which is the rate limiting enzyme of long-chain fatty acid synthesis. In conclusion, VPA supplementation altered lipid metabolism, especially fatty acid oxidation and lipid synthesis, in cisplatin-treated MDA-MB-231 TNBC cells. This metabolic reprogramming might reduce cisplatin resistance. This finding may lead to the discovery of new therapeutic targets, which might reduce side effects and counter drug tolerance in TNBC patients. Frontiers Media S.A. 2022-12-05 /pmc/articles/PMC9760697/ /pubmed/36544904 http://dx.doi.org/10.3389/fcell.2022.1014798 Text en Copyright © 2022 Granit, Mishra, Barasch, Peretz-Yablonsky, Eyal and Kakhlon. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Granit, Avital
Mishra, Kumudesh
Barasch, Dinorah
Peretz-Yablonsky, Tamar
Eyal, Sara
Kakhlon, Or
Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title_full Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title_fullStr Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title_full_unstemmed Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title_short Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
title_sort metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760697/
https://www.ncbi.nlm.nih.gov/pubmed/36544904
http://dx.doi.org/10.3389/fcell.2022.1014798
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