PMID- 30356007
OWN - NLM
STAT- MEDLINE
DCOM- 20181221
LR  - 20181221
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 23
IP  - 11
DP  - 2018 Oct 24
TI  - The Low Molecular Weight Heparin Tinzaparin Attenuates Platelet Activation in 
      Terms of Metastatic Niche Formation by Coagulation-Dependent and Independent 
      Pathways.
LID - 10.3390/molecules23112753 [doi]
LID - 2753
AB  - An intimate interplay with platelets is an initial key issue for tumor cells in 
      terms of hematogenous metastasis. Tumor cells activate platelets by different 
      pathways and receive, upon forming a platelet cloak, protection from immune 
      surveillance and support in metastatic niche creation. Therapeutic intervention 
      with this early interaction is promising to antagonize the whole metastatic 
      cascade. Here we aimed to investigate the capability of low molecular weight 
      heparin (LMWH), unfractionated heparin (UFH), and a non-anticoagulant heparin 
      derivative or FXa inhibitor fondaparinux to interfere with platelet activation by 
      tumor cells. Coagulation-dependent and independent pathways of platelet 
      activation by three tumor cell lines, and interference therewith were analyzed by 
      fluorigenic thrombin formation assay, platelet aggregometry, ATP and VEGF release 
      and endothelial tube formation assay. LMWH and UFH were found to repress various 
      routes of platelet activation, reflected by attenuated endothelial tube 
      formation. This confirms the duality of anti-coagulative and anti-adhesive 
      properties of heparin. While non-anticoagulative heparin (RO-heparin) depressed 
      platelets' ATP and VEGF release by contact inhibition sufficiently, fondaparinux 
      just attenuated tissue factor mediated thrombin generation. Concluding, these 
      data suggest that LMWH as a guideline-based drug for anticoagulative strategies 
      in oncology is promising to provide additional benefit for interference with 
      metastatic activities.
FAU - Gockel, Lukas Maria
AU  - Gockel LM
AD  - Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany. 
      Lukas.Gockel@uni-bonn.de.
FAU - Ponert, Jan Moritz
AU  - Ponert JM
AD  - Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany. 
      moritz.ponert@uni-bonn.de.
FAU - Schwarz, Svenja
AU  - Schwarz S
AD  - Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany. 
      svenja.schwarz@uni-bonn.de.
FAU - Schlesinger, Martin
AU  - Schlesinger M
AD  - Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany. 
      martin.schlesinger@uni-bonn.de.
FAU - Bendas, Gerd
AU  - Bendas G
AD  - Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany. 
      gbendas@uni-bonn.de.
LA  - eng
PT  - Journal Article
DEP - 20181024
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 7UQ7X4Y489 (Tinzaparin)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Blood Coagulation/*drug effects
MH  - Blood Platelets/drug effects/metabolism
MH  - Cell Line, Tumor
MH  - Heparin, Low-Molecular-Weight/chemistry/*pharmacology
MH  - Humans
MH  - Platelet Activation/*drug effects
MH  - Platelet Aggregation/drug effects
MH  - Signal Transduction/*drug effects
MH  - Thrombin/biosynthesis
MH  - Tinzaparin/chemistry/*pharmacology
MH  - Vascular Endothelial Growth Factor A/biosynthesis
PMC - PMC6278400
OTO - NOTNLM
OT  - VEGF
OT  - heparin
OT  - metastatic niche
OT  - platelet
OT  - thrombin
OT  - tumor
COIS- The authors declare no conflict of interest. The founding sponsor had no role in 
      the design of the study; in the collection, analyses, or interpretation of data; 
      in writing of the manuscript, and in the decision to publish the results.
EDAT- 2018/10/26 06:00
MHDA- 2018/12/24 06:00
PMCR- 2018/10/24
CRDT- 2018/10/26 06:00
PHST- 2018/09/26 00:00 [received]
PHST- 2018/10/18 00:00 [revised]
PHST- 2018/10/23 00:00 [accepted]
PHST- 2018/10/26 06:00 [entrez]
PHST- 2018/10/26 06:00 [pubmed]
PHST- 2018/12/24 06:00 [medline]
PHST- 2018/10/24 00:00 [pmc-release]
AID - molecules23112753 [pii]
AID - molecules-23-02753 [pii]
AID - 10.3390/molecules23112753 [doi]
PST - epublish
SO  - Molecules. 2018 Oct 24;23(11):2753. doi: 10.3390/molecules23112753.