Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells

Publication type:
Journal article
Metadata:
Autoren
  • Ching-Fen Wu
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000357138300020&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1021/acs.jnatprod.5b00158
eISSN
1520-6025
Externe Identifier
  • Clarivate Analytics Document Solution ID: CL7FQ
  • PubMed Identifier: 26035463
ISSN
0163-3864
Ausgabe der Veröffentlichung
6
Zeitschrift
JOURNAL OF NATURAL PRODUCTS
Paginierung
1339 - 1347
Datum der Veröffentlichung
2015
Status
Published
Titel
Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells
Sub types
  • Article
Ausgabe der Zeitschrift
78

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Ching-Fen Wu
  • Thomas Efferth
DOI
10.1021/acs.jnatprod.5b00158
eISSN
1520-6025
ISSN
0163-3864
Ausgabe der Veröffentlichung
6
Zeitschrift
Journal of Natural Products
Sprache
en
Online publication date
2015
Paginierung
1339 - 1347
Datum der Veröffentlichung
2015
Status
Published
Herausgeber
American Chemical Society (ACS)
Herausgeber URL
http://dx.doi.org/10.1021/acs.jnatprod.5b00158
Datum der Datenerfassung
2023
Titel
Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells
Ausgabe der Zeitschrift
78

Data source: Crossref

Abstract
Miltirone (1) is a diterpene quinone extracted from a well-known Chinese traditional herb (Salvia miltiorrhiza). We investigated the cytotoxic effects of miltirone toward sensitive and multidrug-resistant acute lymphoblastic leukemia cell lines. Miltirone inhibited multidrug-resistant P-glycoprotein (P-gp)-overexpressing CEM/ADR5000 cells better than drug-sensitive CCRF-CEM wild-type cells, a phenomenon termed collateral sensitivity. Flow cytometric analyses revealed that miltirone induced G2/M arrest and apoptosis. Furthermore, miltirone stimulated reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) disruption, which in turn induced DNA damage and activation of caspases and poly ADP-ribose polymerase (PARP). Downregulation of CCNB1 (cyclin B1) and CDC2 mRNA and upregulation of CDKN1A (p21) mRNA were in accord with miltirone-induced G2/M arrest. Moreover, miltirone decreased cell adherence to fibronectin. Molecular docking revealed that miltirone bound to the ATP-binding site of IKK-β. In conclusion, miltirone was collateral sensitive in multidrug-resistant P-gp-overexpressing cells, induced G2/M arrest, and triggered apoptosis via ROS-generated breakdown of MMP and DNA damage. Therefore, miltirone may be a promising candidate for cancer chemotherapy.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.
Autoren
DOI
10.1021/acs.jnatprod.5b00158
eISSN
1520-6025
Externe Identifier
  • PubMed Identifier: 26035463
Funding acknowledgements
  • National Science Council Taiwan:
  • German Academic Exchange Service:
Open access
false
ISSN
0163-3864
Ausgabe der Veröffentlichung
6
Zeitschrift
Journal of natural products
Schlüsselwörter
  • Humans
  • Salvia miltiorrhiza
  • Reactive Oxygen Species
  • Phenanthrenes
  • Caspases
  • Apoptosis
  • Molecular Structure
  • Cyclin-Dependent Kinase Inhibitor p21
  • Membrane Potential, Mitochondrial
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • G2 Phase Cell Cycle Checkpoints
  • ATP Binding Cassette Transporter, Subfamily B
Sprache
eng
Medium
Print-Electronic
Online publication date
2015
Paginierung
1339 - 1347
Datum der Veröffentlichung
2015
Status
Published
Datum der Datenerfassung
2015
Titel
Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
78

Data source: Europe PubMed Central

Abstract
Miltirone (1) is a diterpene quinone extracted from a well-known Chinese traditional herb (Salvia miltiorrhiza). We investigated the cytotoxic effects of miltirone toward sensitive and multidrug-resistant acute lymphoblastic leukemia cell lines. Miltirone inhibited multidrug-resistant P-glycoprotein (P-gp)-overexpressing CEM/ADR5000 cells better than drug-sensitive CCRF-CEM wild-type cells, a phenomenon termed collateral sensitivity. Flow cytometric analyses revealed that miltirone induced G2/M arrest and apoptosis. Furthermore, miltirone stimulated reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) disruption, which in turn induced DNA damage and activation of caspases and poly ADP-ribose polymerase (PARP). Downregulation of CCNB1 (cyclin B1) and CDC2 mRNA and upregulation of CDKN1A (p21) mRNA were in accord with miltirone-induced G2/M arrest. Moreover, miltirone decreased cell adherence to fibronectin. Molecular docking revealed that miltirone bound to the ATP-binding site of IKK-β. In conclusion, miltirone was collateral sensitive in multidrug-resistant P-gp-overexpressing cells, induced G2/M arrest, and triggered apoptosis via ROS-generated breakdown of MMP and DNA damage. Therefore, miltirone may be a promising candidate for cancer chemotherapy.
Autoren
  • Ching-Fen Wu
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26035463
DOI
10.1021/acs.jnatprod.5b00158
eISSN
1520-6025
Ausgabe der Veröffentlichung
6
Zeitschrift
J Nat Prod
Schlüsselwörter
  • ATP Binding Cassette Transporter, Subfamily B
  • Apoptosis
  • Caspases
  • Cyclin-Dependent Kinase Inhibitor p21
  • G2 Phase Cell Cycle Checkpoints
  • Humans
  • Membrane Potential, Mitochondrial
  • Molecular Structure
  • Phenanthrenes
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Reactive Oxygen Species
  • Salvia miltiorrhiza
Sprache
eng
Country
United States
Paginierung
1339 - 1347
Datum der Veröffentlichung
2015
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2015
Titel
Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
78

Data source: PubMed

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