TY - JOUR
T1 - Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation
AU - Shyu, Kou Gi
AU - Velusamy, Marappan
AU - Hsia, Chih Wei
AU - Yang, Chih Hao
AU - Hsia, Chih Hsuan
AU - Chou, Duen Suey
AU - Jayakumar, Thanasekaran
AU - Sheu, Joen Rong
AU - Li, Jiun Yi
N1 - Funding Information:
The present study was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 104-2622-B-038-003, MOST 104-2320-B-038-045-MY2 and MOST 106-2320-B-038-012), Shin Kong Wu Ho-Su Memorial Hospital-Taipei Medical University (SKH-TMU-103-01), and the University Grants Commission, India (MRP-MAJOR-C HEM-2013-5144; 69/2014 F. No. 10-11/12UGC).
Funding Information:
The present study was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 104-2622-B-038-003, MOST 104-2320-B-038-045-MY2 and MOST 106-2320-B-038-012), Shin Kong Wu Ho-Su Memorial Hospital-Taipei Medical University (SKH-TMU-103-01), and the University Grants commission, India (MRP-MAJOR-cHEM-2013-5144; 69/2014 F. No. 10-11/12UGc).
Publisher Copyright:
© 2018 Spandidos Publications. All rights reserved.
PY - 2018/5
Y1 - 2018/5
N2 - Since cisplatin achieved clinical success, transition metal platinum (Pt) drugs have been effectively used for the treatment of cancer. Iridium (Ir) compounds are considered to be potential alternatives to Pt compounds, as they possess promising anticancer effects with minor side effects. Platelet activation is associated with the metastasis and progression of cancer, and also with arterial thrombosis. Therefore, it is necessary to develop novel, effective antithrombotic agents. An Ir (III)-derived complex, [Ir (Cp∗) 1-(2-pyridyl)-3-(3-methoxyphenyl) imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), was developed as a novel antiplatelet drug. Ir-3 exerted more potent inhibitory activity on platelet aggregation stimulated by collagen compared with other agonists, including thrombin. In collagen-activated platelets, Ir-3 also inhibited adenosine trisphosphate release, intracellular Ca+2 mobilization and surface P-selectin expression, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) 1, but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinases. Ir-3 did not markedly affect phorbol 12, 13-dibutyrate-stimulated platelet aggregation. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one significantly reversed the Ir-3-mediated inhibition of platelet aggregation. Furthermore, Ir-3 had no considerable diminishing effects on OH radical signals in collagen-stimulated platelets or Fenton reaction solution. In conclusion, Ir-3 serves a novel function in the inhibition of platelet aggregation through inhibiting the PLCγ2-PKC cascade, and the subsequent suppression of Akt and JNK1 activation. Therefore, Ir-3 may be a potential novel therapeutic agent for the treatment of thromboembolic disorders, or the interplay between platelets and tumor cells which contributes to tumor cell proliferation and progression.
AB - Since cisplatin achieved clinical success, transition metal platinum (Pt) drugs have been effectively used for the treatment of cancer. Iridium (Ir) compounds are considered to be potential alternatives to Pt compounds, as they possess promising anticancer effects with minor side effects. Platelet activation is associated with the metastasis and progression of cancer, and also with arterial thrombosis. Therefore, it is necessary to develop novel, effective antithrombotic agents. An Ir (III)-derived complex, [Ir (Cp∗) 1-(2-pyridyl)-3-(3-methoxyphenyl) imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), was developed as a novel antiplatelet drug. Ir-3 exerted more potent inhibitory activity on platelet aggregation stimulated by collagen compared with other agonists, including thrombin. In collagen-activated platelets, Ir-3 also inhibited adenosine trisphosphate release, intracellular Ca+2 mobilization and surface P-selectin expression, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) 1, but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinases. Ir-3 did not markedly affect phorbol 12, 13-dibutyrate-stimulated platelet aggregation. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one significantly reversed the Ir-3-mediated inhibition of platelet aggregation. Furthermore, Ir-3 had no considerable diminishing effects on OH radical signals in collagen-stimulated platelets or Fenton reaction solution. In conclusion, Ir-3 serves a novel function in the inhibition of platelet aggregation through inhibiting the PLCγ2-PKC cascade, and the subsequent suppression of Akt and JNK1 activation. Therefore, Ir-3 may be a potential novel therapeutic agent for the treatment of thromboembolic disorders, or the interplay between platelets and tumor cells which contributes to tumor cell proliferation and progression.
KW - C-Jun N-terminal kinase 1
KW - Ir (III)-derived complex
KW - Phospholipase Cγ2-protein kinase C cascade
KW - Platelet activation
KW - Protein kinase B
KW - P-Selectin/metabolism
KW - Blood Platelets/cytology
KW - Humans
KW - Iridium/chemistry
KW - Adenosine Triphosphate/metabolism
KW - Organometallic Compounds/chemistry
KW - Phospholipase C gamma/metabolism
KW - Platelet Activation/drug effects
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Signal Transduction/drug effects
KW - Calcium/metabolism
KW - Platelet Aggregation Inhibitors/chemistry
KW - Protein Kinase C/metabolism
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U2 - 10.3892/ijmm.2018.3472
DO - 10.3892/ijmm.2018.3472
M3 - Article
C2 - 29436605
AN - SCOPUS:85042798273
SN - 1107-3756
VL - 41
SP - 2589
EP - 2600
JO - International Journal of Molecular Medicine
JF - International Journal of Molecular Medicine
IS - 5
ER -