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Int. J. Mol. Sci. 2017, 18(12), 2616; https://doi.org/10.3390/ijms18122616

New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound

1
Department of Pharmacology and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250Wu-Hsing Street, Taipei 110, Taiwan
2
Department of Chemistry, North Eastern Hill University, Shillong 793022, India
3
Division of Allergy and Immunology, Department of Internal Medicine, Cathay General Hospital, Taipei 106, Taiwan
4
Department of Microbiology and Immunology, Taipei Medical University, Taipei 110, Taiwan
5
Department of Cardiovascular Surgery, Mackay Memorial Hospital, and Mackay Medical College, Taipei 104, Taiwan
These authors contributed equally to this work.
Current address: Division of General Internal Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 112, Taiwan.
*
Author to whom correspondence should be addressed.
Received: 12 October 2017 / Revised: 15 November 2017 / Accepted: 29 November 2017 / Published: 5 December 2017
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Abstract

Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2–PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells. View Full-Text
Keywords: Ir(III)-derived complex; platelet activation; protein kinases; OH· free radical; bleeding time; pulmonary thromboembolism Ir(III)-derived complex; platelet activation; protein kinases; OH· free radical; bleeding time; pulmonary thromboembolism
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Hsia, C.-W.; Velusamy, M.; Tsao, J.-T.; Hsia, C.-H.; Chou, D.-S.; Jayakumar, T.; Lee, L.-W.; Li, J.-Y.; Sheu, J.-R. New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound. Int. J. Mol. Sci. 2017, 18, 2616.

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