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New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound
- 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.
- Subjects :
- 0301 basic medicine
Platelet Aggregation
Pharmacology
Phospholipase
Iridium
Catalysis
Article
Inorganic Chemistry
lcsh:Chemistry
03 medical and health sciences
chemistry.chemical_compound
bleeding time
0302 clinical medicine
Ir(III)-derived complex
Organometallic Compounds
platelet activation
Humans
Platelet
pulmonary thromboembolism
Platelet activation
Physical and Theoretical Chemistry
Molecular Biology
Protein kinase B
lcsh:QH301-705.5
Spectroscopy
Protein kinase C
Protein Kinase C
protein kinases
Kinase
Phospholipase C gamma
Organic Chemistry
OH· free radical
Thrombosis
General Medicine
Computer Science Applications
030104 developmental biology
chemistry
lcsh:Biology (General)
lcsh:QD1-999
030220 oncology & carcinogenesis
Phosphorylation
Mitogen-Activated Protein Kinases
Adenosine triphosphate
Platelet Aggregation Inhibitors
Subjects
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