title: Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis.
abstract: Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCμ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Chang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Yu-Tsui
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Meng-Hong
authors.initials: MH
authors.lastname: Lu
authors.affiliation: Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei 104, Taiwan, Republic of China (ROC).
authors.forename: Tur-Fu
authors.initials: TF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Kowit-Yu
authors.initials: KY
authors.lastname: Chong
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Hsiang-Ruei
authors.initials: HR
authors.lastname: Liao
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan, Republic of China (ROC).
authors.forename: Ju-Chien
authors.initials: JC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC).|Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China (ROC).
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000473:pathology; D009579:Nitrobenzoates / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
chemical_list: D000970:Antineoplastic Agents; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009579:Nitrobenzoates; D010975:Platelet Aggregation Inhibitors; C104778:CLEC2B protein, human; C117468:PDPN protein, human; D000098853:Podoplanin
keywords: TCIPA; platelet aggregation; podoplanin; tumor metastasis