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

Authors :
Chih Hsuan Hsia
Joen Rong Sheu
Lin Wen Lee
Jeng Ting Tsao
Jiun Yi Li
Duen Suey Chou
Marappan Velusamy
Chih Wei Hsia
Thanasekaran Jayakumar
Source :
International Journal of Molecular Sciences; Volume 18; Issue 12; Pages: 2616, International Journal of Molecular Sciences, Vol 18, Iss 12, p 2616 (2017), International Journal of Molecular Sciences
Publication Year :
2017
Publisher :
Multidisciplinary Digital Publishing Institute, 2017.

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.

Details

Language :
English
ISSN :
14220067
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences; Volume 18; Issue 12; Pages: 2616
Accession number :
edsair.doi.dedup.....9381a7391bab24bd1cd5a9f221b5b093
Full Text :
https://doi.org/10.3390/ijms18122616