{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:12:23Z","timestamp":1760242343578,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T00:00:00Z","timestamp":1493251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"MOST","doi-asserted-by":"publisher","award":["MOST103-2320-B-038-017, OST104-2622-B-038-003, and MOST 104-2320-B-038-045-MY2"],"award-info":[{"award-number":["MOST103-2320-B-038-017, OST104-2622-B-038-003, and MOST 104-2320-B-038-045-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yuan's General Hospital-Taipei Medical University","award":["104-YGH-TMU-01-3"],"award-info":[{"award-number":["104-YGH-TMU-01-3"]}]},{"name":"UGC, MRP-MAJOR-CHEM-2013-5144","award":["69\/2014 F.No. 10-11\/12"],"award-info":[{"award-number":["69\/2014 F.No. 10-11\/12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In oncotherapy, ruthenium complexes are considered as potential alternatives for platinum compounds, and have been proved as promising anticancer drugs with high efficacy and lesser side effects. Platelet activation plays a major role in cancer metastasis and progression. Hence, this study explored the effect of a newly synthesized ruthenium complex, [Ru(\u03b76-cymene)(L)Cl]BF4(TQ5), where L = 4-phenyl-2-pyridin-2-yl-quinazoline), on human platelet activation. TQ5 (3\u20135 \u00b5M) inhibited concentration-dependent collagen-induced platelet aggregation in washed human platelets. However, this compound only inhibited platelet aggregation at a maximum concentration of 500 and 100 \u00b5M against thrombin and 9,11-dideoxy-11\u03b1, 9\u03b1-epoxymethanoprostaglandin (U46619)-induced stimulation, respectively. TQ5 inhibited collagen-induced ATP release and calcium mobilization ([Ca2+]i), without inducing cell cytotoxicity. In addition, neither SQ22536, an adenylate cyclase inhibitor, nor 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, significantly reversed the TQ5-mediated inhibition of platelet aggregation. TQ5 inhibited the collagen-induced phosphorylation of protein kinase B (Akt) and c-Jun N-terminal kinase (JNK), but did not effectively inhibit extracellular signal-regulated kinase 1\/2 (ERK1\/2) and p38-mitogen-activated protein kinase (p38-MAPK) in human platelets. Additionally, TQ5 significantly prolonged the closure time in whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. This study demonstrates, for the first time, that a newly synthesized ruthenium complex, TQ5, exhibits potent antiplatelet activity by hindering ATP release and [Ca2+]i, and by decreasing the activation of Akt\/JNK signals. Together, these results suggest that TQ5 could be developed as a therapeutic agent that helps prevent or treat thromboembolic disorders, since it is found to be potently more effective than a well-established antithrombotic aspirin.<\/jats:p>","DOI":"10.3390\/ijms18050916","type":"journal-article","created":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T13:01:15Z","timestamp":1493298075000},"page":"916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Antiplatelet Activity of a Newly Synthesized Novel Ruthenium (II): A Potential Role for Akt\/JNK Signaling"],"prefix":"10.3390","volume":"18","author":[{"given":"Themmila","family":"Khamrang","sequence":"first","affiliation":[{"name":"Department of Chemistry, North Eastern Hill University, Shillong 793022, India"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo-Chen","family":"Hung","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Gastroenterologic Surgery Division, Department of Surgery, Yuan\u2019s General Hospital, Kaohsiung 249, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Hsuan","family":"Hsia","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Ying","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marappan","family":"Velusamy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, North Eastern Hill University, Shillong 793022, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanasekaran","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1055\/s-2004-822974","article-title":"Platelets and angiogenesis in malignancy","volume":"30","author":"Sierko","year":"2004","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/ijc.2910600324","article-title":"The effect of platelets on invasiveness and protease production of human mammary tumor cells","volume":"60","author":"Belloc","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1073\/pnas.98.4.1853","article-title":"Integrin activation controls metastasis in human breast cancer","volume":"98","author":"Ooole","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s10585-009-9264-9","article-title":"Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis","volume":"26","author":"Holmes","year":"2009","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1172\/JCI200422123","article-title":"Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer","volume":"114","author":"Boucharaba","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"C239","DOI":"10.1152\/ajpcell.1997.273.1.C239","article-title":"Thrombin promotes endothelial cell alignment in Matrigel in vitro and angiogenesis in vivo","volume":"273","author":"Haralabopoulos","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1093\/jnci\/85.15.1225","article-title":"Tumor cell procoagulant and urokinase expression in carcinoma of the ovary","volume":"85","author":"Zacharski","year":"1993","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_8","first-page":"541","article-title":"Human tumor cells cultured \u201cin vitro\u201d activate platelet function by producing ADP or thrombin","volume":"74","author":"Zucchella","year":"1989","journal-title":"Haematologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/BF02573067","article-title":"Poor prognosis associated with thrombocytosis in patients with gastric cancer","volume":"9","author":"Ikeda","year":"2002","journal-title":"Ann. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1055\/s-0037-1615093","article-title":"Platelet count and survival in patients with colorectal cancer\u2014A preliminary study","volume":"79","author":"Monreal","year":"1998","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1464-410x.2000.00792.x","article-title":"Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma","volume":"86","author":"Symbas","year":"2000","journal-title":"BJU Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1055\/s-0038-1642691","article-title":"Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo","volume":"74","author":"Nierodzik","year":"1995","journal-title":"Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10585-009-9299-y","article-title":"Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions","volume":"27","author":"Wenzel","year":"2010","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"406","DOI":"10.2174\/092986712803414240","article-title":"New perspectives in antiplatelet therapy","volume":"19","author":"Jover","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1182\/blood-2007-04-085514","article-title":"The role of Akt in the signaling pathway of the lycoprotein Ib-IX induced platelet activation","volume":"111","author":"Yin","year":"2008","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.vph.2014.10.005","article-title":"Antiplatelet action of indirubin-3\u2032-monoxime through suppression of glycoprotein VI-mediated signal transduction: A possible role for ERK signaling in platelets","volume":"63","author":"Lee","year":"2014","journal-title":"Vascul. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cbpa.2007.11.013","article-title":"New trends for metal complexes with anticancer activity","volume":"12","author":"Bruijnincx","year":"2008","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrc2167","article-title":"The resurgence of platinum-based cancer chemotherapy","volume":"7","author":"Kelland","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6858","DOI":"10.1021\/jm060596m","article-title":"Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands","volume":"49","author":"Habtemariam","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.biomaterials.2014.10.057","article-title":"Nanodiamonds coupled with plant bioactive metabolites: A nanotech approach for cancer therapy","volume":"38","author":"Gismondi","year":"2015","journal-title":"Biomaterials"},{"key":"ref_21","first-page":"395637","article-title":"Chemical characteristics, synthetic methods, and biological potential of quinazoline and quinazolinone derivatives","volume":"2014","author":"Asif","year":"2014","journal-title":"Int. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6058","DOI":"10.1016\/j.ejmech.2010.10.008","article-title":"Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6-disubstituted-1,2,3,4-tetrahydroquinazolin-2H-ones","volume":"45","author":"Gawad","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12152","DOI":"10.1002\/chem.201301389","article-title":"Ruthenium-arene-\u03b2-carboline complexes as potent inhibitors of cyclin dependent kinase 1: Synthesis, characterization and anticancer mechanism studies","volume":"19","author":"He","year":"2013","journal-title":"Chem. Eur. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1039\/B303737A","article-title":"Room-temperature cyclometallation of amines, imines and oxazolines with [MCl2Cp*]2 (M = Rh, Ir) and [RuCl2( p-cymene)]2","volume":"21","author":"Davies","year":"2003","journal-title":"Dalton Trans."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1067\/mlc.2001.117406","article-title":"Platelet function analyzer (PFA-100): A tool to quantify congenital or acquired platelet dysfunction","volume":"138","author":"Jilma","year":"2001","journal-title":"J. Lab. Clin. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1470-2045(01)00619-2","article-title":"Cancer and the prothrombotic state","volume":"3","author":"Lip","year":"2002","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"895729","DOI":"10.1155\/2012\/895729","article-title":"Pistacia chinensis Methanolic Extract Attenuated MAPK and Akt Phosphorylations in ADP Stimulated Rat Platelets In Vitro","volume":"2012","author":"Park","year":"2012","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1089\/rej.2010.1141","article-title":"Platinum-based compounds and risk for cardiovascular toxicity in the elderly: Role of the antioxidants in chemoprevention","volume":"14","author":"Ferroni","year":"2011","journal-title":"Rejuvenation Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1097\/CAD.0b013e3283100e9c","article-title":"Cisplatin-associated thrombosis","volume":"19","author":"Jafri","year":"2008","journal-title":"Anticancer Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/1479-5876-9-179","article-title":"Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: Results of a retrospective analysis of the PROTECHT study","volume":"9","author":"Barni","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1517\/14740330802374262","article-title":"Gemcitabine: Vascular toxicity and prothrombotic potential","volume":"7","author":"Dasanu","year":"2008","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4A","DOI":"10.1016\/j.amjcard.2008.11.017","article-title":"Role of platelets in atherothrombosis","volume":"103","author":"Jennings","year":"2009","journal-title":"Am. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/0143-4160(82)90020-3","article-title":"Phosphatidylinositol turnover in platelet activation; calcium mobilization and protein phosphorylation","volume":"3","author":"Kaibuchi","year":"1982","journal-title":"Cell Calcium"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-4615-2994-1_19","article-title":"Role of cyclic nucleotide dependent protein kinases and their common substrate VASP in the regulation of human platelets","volume":"344","author":"Walter","year":"1993","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jnutbio.2015.09.024","article-title":"Prevention of arterial thrombosis by nobiletin: In vitro and in vivo studies","volume":"28","author":"Lu","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1042\/bst0320387","article-title":"Phosphoinositide 3-kinases and the regulation of platelet function","volume":"32","author":"Jackson","year":"2004","journal-title":"Biochem. Soc. Trans."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1074\/jbc.M112.429936","article-title":"Dual regulation of glycogen synthase kinase 3 (GSK3)\u03b1\/\u03b2 by protein kinase C (PKC)\u03b1 and Akt promotes thrombin-mediated integrin \u03b1IIb\u03b23 activation and granule secretion in platelets","volume":"288","author":"Moore","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1160\/TH13-06-0484","article-title":"PDK1 selectively phosphorylates Thr(308) on AKT and contributes to human platelet functional responses","volume":"111","author":"Dangelmaier","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"38903","DOI":"10.1074\/jbc.M405314200","article-title":"Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells","volume":"279","author":"Deb","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood-2003-10-3428","article-title":"Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice","volume":"104","author":"Chen","year":"2004","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4083","DOI":"10.1182\/blood-2009-07-233932","article-title":"Platelet JNK1 is involved in secretion and thrombus formation","volume":"115","author":"Adam","year":"2010","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/35065000","article-title":"Mammalian MAP kinase signalling cascades","volume":"410","author":"Chang","year":"2001","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)81892-9","article-title":"Suppression of integrin activation: A novel function of a Ras\/Raf-initiated MAP kinase pathway","volume":"88","author":"Hughes","year":"1997","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1595\/147106706X111582","article-title":"Phosphoramidite-controlled asymmetric hydrogenation with rhodium catalysts","volume":"50","author":"Ager","year":"2006","journal-title":"Platin. Met. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1039\/b904071d","article-title":"Recent developments in ruthenium anticancer drugs","volume":"1","author":"Levina","year":"2009","journal-title":"Metallomics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1055\/s-0038-1649580","article-title":"Registry of clinical trials of antithrombotic drugs in cancer: Second report. The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Subcommittee on Hemostasis and Malignancy","volume":"70","author":"Zacharski","year":"1993","journal-title":"Thromb. Haemost."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1055\/s-0037-1613907","article-title":"Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets","volume":"83","author":"Sheu","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.bcp.2013.02.027","article-title":"Hinokitiol inhibits platelet activation ex vivo and thrombus formation in vivo","volume":"85","author":"Lin","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1161\/01.ATV.0000174798.25085.d6","article-title":"Protective mechanisms of inosine in platelet activation and cerebral ischemic damage","volume":"25","author":"Hsiao","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/5\/916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:33:55Z","timestamp":1760207635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/5\/916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,27]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["ijms18050916"],"URL":"https:\/\/doi.org\/10.3390\/ijms18050916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2017,4,27]]}}}