Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells

Publication type:
Journal article
Metadata:
Autoren
  • Ching-Fen Wu
  • Chunlan Hong
  • Sabine M Klauck
  • Yun-Lian Lin
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000367106600007&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.jep.2015.10.020
eISSN
1872-7573
Externe Identifier
  • Clarivate Analytics Document Solution ID: CZ4XP
  • PubMed Identifier: 26476154
ISSN
0378-8741
Zeitschrift
JOURNAL OF ETHNOPHARMACOLOGY
Schlüsselwörter
  • Cell death
  • NF kappa B
  • Multidrug resistance
  • Pharmacogenomics
Paginierung
55 - 68
Datum der Veröffentlichung
2015
Status
Published
Titel
Molecular mechanisms of rosmarinic acid from <i>Salvia miltiorrhiza</i> in acute lymphoblastic leukemia cells
Sub types
  • Article
Ausgabe der Zeitschrift
176

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Ching-Fen Wu
  • Chunlan Hong
  • Sabine M Klauck
  • Yun-Lian Lin
  • Thomas Efferth
DOI
10.1016/j.jep.2015.10.020
ISSN
0378-8741
Zeitschrift
Journal of Ethnopharmacology
Sprache
en
Paginierung
55 - 68
Datum der Veröffentlichung
2015
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.jep.2015.10.020
Datum der Datenerfassung
2020
Titel
Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells
Ausgabe der Zeitschrift
176

Data source: Crossref

Abstract
<h4>Ethnopharmacological relevance</h4>Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated.<h4>Aim of the study</h4>Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells.<h4>Materials and methods</h4>Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM, multidrug-resistant CEM/ADR5000 cells and normal lymphocytes), flow cytometry (cell cycle arrest, apoptosis, necroptosis, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP)), single cell gel electrophoresis (DNA damage), molecular docking and gene promoter binding motif analysis (NFκB), Western blotting (nuclear NFκB translocation, PARP cleavage, caspase 3/7/9 expression), and fibronectin-based cell adhesion assay.<h4>Results</h4>RA dose-dependently inhibited CCRF-CEM and CEM/ADR5000 cells, but caused less cytotoxicity towards normal lymphocytes. RA simultaneously induced apoptosis and necrosis, as shown by cell morphology and annexin V-PI assay. DNA damage was dose-dependently induced without ROS generation, which subsequently led to cell cycle arrest. RA-stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis. In accordance with molecular docking and gene promoter binding motif analyses, p65 translocation from the cytosol to the nucleus was blocked by RA, indicating a mechanistic role of the NFκB pathway to explain RA's action. RA affected cellular movement as evaluated by ameliorating cell adhesion to fibronectin.<h4>Conclusions</h4>RA induced apoptosis and necrosis in a ROS-independent DNA damage and caspase-independent manner. These results may contribute to the rationale use of S. miltiorrhiza and RA in traditional medicine of leukemia.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
  • Ching-Fen Wu
  • Chunlan Hong
  • Sabine M Klauck
  • Yun-Lian Lin
  • Thomas Efferth
  • Thomas Efferth
DOI
10.1016/j.jep.2015.10.020
eISSN
1872-7573
Externe Identifier
  • PubMed Identifier: 26476154
Funding acknowledgements
  • microarray unit of the DKFZ:
  • Cytometry Core Facility in IMB (Mainz, Germany):
Open access
false
ISSN
0378-8741
Zeitschrift
Journal of ethnopharmacology
Schlüsselwörter
  • Lymphocytes
  • Cells, Cultured
  • Cell Line, Tumor
  • Humans
  • Salvia miltiorrhiza
  • DNA Damage
  • Reactive Oxygen Species
  • Cinnamates
  • NF-kappa B
  • Antineoplastic Agents
  • Comet Assay
  • Gene Expression Profiling
  • Drug Resistance, Multiple
  • Cell Adhesion
  • Cell Cycle
  • Apoptosis
  • Cell Survival
  • Drug Resistance, Neoplasm
  • Depsides
  • Membrane Potential, Mitochondrial
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Molecular Docking Simulation
  • Rosmarinic Acid
Sprache
eng
Medium
Print-Electronic
Online publication date
2015
Paginierung
55 - 68
Datum der Veröffentlichung
2015
Status
Published
Datum der Datenerfassung
2015
Titel
Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
176

Data source: Europe PubMed Central

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated. AIM OF THE STUDY: Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells. MATERIALS AND METHODS: Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM, multidrug-resistant CEM/ADR5000 cells and normal lymphocytes), flow cytometry (cell cycle arrest, apoptosis, necroptosis, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP)), single cell gel electrophoresis (DNA damage), molecular docking and gene promoter binding motif analysis (NFκB), Western blotting (nuclear NFκB translocation, PARP cleavage, caspase 3/7/9 expression), and fibronectin-based cell adhesion assay. RESULTS: RA dose-dependently inhibited CCRF-CEM and CEM/ADR5000 cells, but caused less cytotoxicity towards normal lymphocytes. RA simultaneously induced apoptosis and necrosis, as shown by cell morphology and annexin V-PI assay. DNA damage was dose-dependently induced without ROS generation, which subsequently led to cell cycle arrest. RA-stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis. In accordance with molecular docking and gene promoter binding motif analyses, p65 translocation from the cytosol to the nucleus was blocked by RA, indicating a mechanistic role of the NFκB pathway to explain RA's action. RA affected cellular movement as evaluated by ameliorating cell adhesion to fibronectin. CONCLUSIONS: RA induced apoptosis and necrosis in a ROS-independent DNA damage and caspase-independent manner. These results may contribute to the rationale use of S. miltiorrhiza and RA in traditional medicine of leukemia.
Date of acceptance
2015
Autoren
  • Ching-Fen Wu
  • Chunlan Hong
  • Sabine M Klauck
  • Yun-Lian Lin
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26476154
DOI
10.1016/j.jep.2015.10.020
eISSN
1872-7573
Zeitschrift
J Ethnopharmacol
Schlüsselwörter
  • Cell death
  • Multidrug resistance
  • NFκB
  • Pharmacogenomics
  • Antineoplastic Agents
  • Apoptosis
  • Cell Adhesion
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Survival
  • Cells, Cultured
  • Cinnamates
  • Comet Assay
  • DNA Damage
  • Depsides
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Gene Expression Profiling
  • Humans
  • Lymphocytes
  • Membrane Potential, Mitochondrial
  • Molecular Docking Simulation
  • NF-kappa B
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Reactive Oxygen Species
  • Salvia miltiorrhiza
  • Rosmarinic Acid
Sprache
eng
Country
Ireland
Paginierung
55 - 68
PII
S0378-8741(15)30180-X
Datum der Veröffentlichung
2015
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2016
Titel
Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
176

Data source: PubMed

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