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

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          Abstract

          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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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights

            Since its first release over a decade ago, the MetaboAnalyst web-based platform has become widely used for comprehensive metabolomics data analysis and interpretation. Here we introduce MetaboAnalyst version 5.0, aiming to narrow the gap from raw data to functional insights for global metabolomics based on high-resolution mass spectrometry (HRMS). Three modules have been developed to help achieve this goal, including: (i) a LC–MS Spectra Processing module which offers an easy-to-use pipeline that can perform automated parameter optimization and resumable analysis to significantly lower the barriers to LC-MS1 spectra processing; (ii) a Functional Analysis module which expands the previous MS Peaks to Pathways module to allow users to intuitively select any peak groups of interest and evaluate their enrichment of potential functions as defined by metabolic pathways and metabolite sets; (iii) a Functional Meta-Analysis module to combine multiple global metabolomics datasets obtained under complementary conditions or from similar studies to arrive at comprehensive functional insights. There are many other new functions including weighted joint-pathway analysis, data-driven network analysis, batch effect correction, merging technical replicates, improved compound name matching, etc. The web interface, graphics and underlying codebase have also been refactored to improve performance and user experience. At the end of an analysis session, users can now easily switch to other compatible modules for a more streamlined data analysis. MetaboAnalyst 5.0 is freely available at https://www.metaboanalyst.ca . Graphical Abstract From raw data to statistical and functional insights using MetaboAnalyst 5.0.
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              Triple-negative breast cancer molecular subtyping and treatment progress

              Triple-negative breast cancer (TNBC), a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), has clinical features that include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Because TNBC tumors lack ER, PR, and HER2 expression, they are not sensitive to endocrine therapy or HER2 treatment, and standardized TNBC treatment regimens are still lacking. Therefore, development of new TNBC treatment strategies has become an urgent clinical need. By summarizing existing treatment regimens, therapeutic drugs, and their efficacy for different TNBC subtypes and reviewing some new preclinical studies and targeted treatment regimens for TNBC, this paper aims to provide new ideas for TNBC treatment.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                05 December 2022
                2022
                : 10
                : 1014798
                Affiliations
                [1] 1 Sharett Institute of Oncology , Hadassah-Hebrew University Medical Center , Jerusalem, Israel
                [2] 2 Institute for Drug Research School of Pharmacy , The Hebrew University of Jerusalem , Jerusalem, Israel
                [3] 3 Department of Neurology , Hadassah-Hebrew University Medical Center , Jerusalem, Israel
                [4] 4 Faculty of Medicine , Hebrew University of Jerusalem , Jerusalem, Israel
                [5] 5 Mass Spectrometry Unit , Institute for Drug Research , School of Pharmacy , The Hebrew University of Jerusalem , Jerusalem, Israel
                [6] 6 The Dame Susan Garth Chair of Cancer Research , The David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem , Jerusalem, Israel
                Author notes

                Edited by: Suneel Kateriya, Jawaharlal Nehru University, India

                Reviewed by: Mariafrancesca Scalise, University of Calabria, Italy

                José Ignacio Ruiz-Sanz, University of the Basque Country, Spain

                *Correspondence: Sara Eyal, sarae@ 123456ekmd.huji.ac.il ; Or Kakhlon, ork@ 123456hadassah.org.il

                This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                1014798
                10.3389/fcell.2022.1014798
                9760697
                36544904
                4ea52b14-3e2c-44e8-a2e2-45cc7b4047b8
                Copyright © 2022 Granit, Mishra, Barasch, Peretz-Yablonsky, Eyal and Kakhlon.

                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.

                History
                : 09 August 2022
                : 31 October 2022
                Categories
                Cell and Developmental Biology
                Brief Research Report

                valproic acid,metabolomics,metabolism,cisplalin,triple negative breast cancer

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