PMID- 29953653
OWN - NLM
STAT- MEDLINE
DCOM- 20191010
LR  - 20191010
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 119
IP  - 11
DP  - 2018 Nov
TI  - Valproic acid inhibits the protective effects of stromal cells against 
      chemotherapy in breast cancer: Insights from proteomics and systems biology.
PG  - 9270-9283
LID - 10.1002/jcb.27196 [doi]
AB  - Interaction between tumor and stromal cells is beginning to be decoded as a 
      contributor to chemotherapy resistance. Here, we aim to take a system-level 
      approach to explore a mechanism by which stromal cells induce chemoresistance in 
      cancer cells and subsequently identify a drug that can inhibit such interaction. 
      Using a proteomic dataset containing quantitative data on secretome of stromal 
      cells, we performed multivariate analyses and found that bone-marrow mesenchymal 
      stem cells (BM-MSCs) play the most protective role against chemotherapeutics. 
      Pathway enrichment tests showed that secreted cytokines from BM-MSCs activated 4 
      signaling pathways including Janus kinase-signal transducer and activator of 
      transcription, phosphatidylinositol 3-kinase-protein kinase B, and 
      mitogen-activated protein kinase, transforming growth factor-beta in cancer cells 
      collectively leading to nuclear factor kappa-light-chain-enhancer of activated B 
      cells (NF-kB) transcription factor activation. Based on the data from integrated 
      Library of Integrated Network-Based Cellular Signatures (iLINCs) program, we 
      found that among different drugs, valproic acid (VA) affected the expression of 
      34 genes within the identified pathways that are activated by stromal cells. Our 
      in vitro experiments confirmed that VA inhibits NF-kB activation in cancer cells. 
      In addition, analyzing gene expression data in patients taking oral VA showed 
      that this drug decreased expression of antioxidant enzymes culminating in 
      increased oxidative stress in tumor cells. These results suggest that VA confines 
      the protective role of stromal cells by inhibiting the adaptation mechanisms 
      toward oxidative stress which is potentiated by stromal cells. Since VA is an 
      already prescribed drug manifesting anticancer effects, this study provides a 
      mechanistic insight for combination of VA with chemotherapy in the clinical 
      setting.
CI  - (c) 2018 Wiley Periodicals, Inc.
FAU - Barneh, Farnaz
AU  - Barneh F
AD  - Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti 
      University of Medical Sciences, Tehran, Iran.
AD  - Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran.
AD  - Drug Design and Bioinformatics Unit, Medical Biotechnology Department, 
      Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
FAU - Salimi, Mona
AU  - Salimi M
AUID- ORCID: 0000-0002-3997-7009
AD  - Physiology and Pharmacology Department, Pasteur Institute of Iran, Tehran, Iran.
FAU - Goshadrou, Fatemeh
AU  - Goshadrou F
AD  - Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti 
      University of Medical Sciences, Tehran, Iran.
FAU - Ashtiani, Minoo
AU  - Ashtiani M
AD  - Drug Design and Bioinformatics Unit, Medical Biotechnology Department, 
      Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
AD  - Department of Computer Science and Statistics, Faculty of Mathematics, K. N. 
      Toosi University of Technology, Tehran, Iran.
FAU - Mirzaie, Mehdi
AU  - Mirzaie M
AD  - Department of Applied Mathematics, Faculty of Mathematical Sciences, Tarbiat 
      Modares University, Tehran, Iran.
FAU - Zali, Hakimeh
AU  - Zali H
AD  - School of Advanced Technologies in Medicine, Shahid Beheshti University of 
      Medical sciences, Tehran, Iran.
FAU - Jafari, Mohieddin
AU  - Jafari M
AUID- ORCID: 0000-0002-6991-8587
AD  - Drug Design and Bioinformatics Unit, Medical Biotechnology Department, 
      Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180628
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (NF-kappa B)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Breast Neoplasms/*metabolism
MH  - Cell Line, Tumor
MH  - Doxorubicin/pharmacology
MH  - Female
MH  - Humans
MH  - Mesenchymal Stem Cells/cytology/drug effects
MH  - NF-kappa B/metabolism
MH  - Proteomics/*methods
MH  - Systems Biology/*methods
MH  - Valproic Acid/*pharmacology
OTO - NOTNLM
OT  - cancer
OT  - drug resistance
OT  - proteomics
OT  - systems biology
OT  - tumor microenvironment
OT  - valproic acid
EDAT- 2018/06/29 06:00
MHDA- 2019/10/11 06:00
CRDT- 2018/06/29 06:00
PHST- 2018/02/01 00:00 [received]
PHST- 2018/05/24 00:00 [accepted]
PHST- 2018/06/29 06:00 [pubmed]
PHST- 2019/10/11 06:00 [medline]
PHST- 2018/06/29 06:00 [entrez]
AID - 10.1002/jcb.27196 [doi]
PST - ppublish
SO  - J Cell Biochem. 2018 Nov;119(11):9270-9283. doi: 10.1002/jcb.27196. Epub 2018 Jun 
      28.