title: Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid inhibits platelet activation and thrombosis via inhibition of thromboxane A2 signaling and phosphodiesterase.
abstract: BACKGROUND
  5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a tumor vascular disrupting agent under clinical trials as an adjacent antitumor agent. DMXAA is structurally similar to flavone-8-acetic acid (FAA), an old tumor vascular disrupting agent with antiplatelet and antithrombotic effects. In contrast to FAA, which causes bleeding in tumor patients, no bleeding has been reported in patients receiving DMXAA. Whether DMXAA also affects platelet function is not clear.
  
  
  OBJECTIVE
  To determine the effects of DMXAA on platelet function and explore the underlying mechanisms.
  
  
  RESULTS
  DMXAA concentration-dependently inhibited human platelet aggregation and ATP release induced by U46619, arachidonic acid, ADP, collagen, or ristocetin. Furthermore, DMXAA inhibited phosphorylation of Erk1/2 and Akt downstream of thromboxane A2 signaling inhibition. DMXAA also inhibited human platelet phosphodiesterase. The antiplatelet effects were further confirmed using mice administered DMXAA intravenously. DMXAA dramatically inhibited thrombus formation in FeCl3 -injured mouse mesenteric arterial thrombus model and laser-injured mouse cremaster arteriole thrombus model. Notably, at a dose exhibiting antithrombotic effects similar to those of clopidogrel in mice, DMXAA did not significantly increase bleeding.
  
  
  CONCLUSIONS
  For the first time, we found that tumor vascular disrupting agent DMXAA has potent antiplatelet and antithrombotic effects without any bleeding diathesis. As DMXAA inhibits platelet activity with safe profile, DMXAA could be used as an efficacious and safe antiplatelet drug.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
authors.forename: S H
authors.initials: SH
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Gu
authors.forename: J S
authors.initials: JS
authors.lastname: Mruk
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: S P
authors.initials: SP
authors.lastname: Kunapuli
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013927:Thrombosis / Q000517:prevention & control*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D044004:Xanthones; C066668:vadimezan; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D013930:Thromboxane-A Synthase
keywords: DMXAA; TXA2; antiplatelet agents; antitumor agents; phosphodiesterase inhibitors