Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation

Kou Gi Shyu, Marappan Velusamy, Chih Wei Hsia, Chih Hao Yang, Chih Hsuan Hsia, Duen Suey Chou, Thanasekaran Jayakumar, Joen Rong Sheu, Jiun Yi Li

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2589-2600
Number of pages12
JournalInternational Journal of Molecular Medicine
Volume41
Issue number5
DOIs
Publication statusPublished - May 1 2018

Fingerprint

Organometallic Compounds
Iridium
Platelet Activation
Platelet Aggregation
Collagen
Blood Platelets
Phospholipases
Neoplasms
Mitogen-Activated Protein Kinase 8
Platinum Compounds
Phorbol 12,13-Dibutyrate
Proto-Oncogene Proteins c-akt
P-Selectin
Fibrinolytic Agents
Guanylate Cyclase
Platelet Aggregation Inhibitors
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Platinum
Thrombin

Keywords

  • C-Jun N-terminal kinase 1
  • Ir (III)-derived complex
  • Phospholipase Cγ2-protein kinase C cascade
  • Platelet activation
  • Protein kinase B
  • P-Selectin/metabolism
  • Blood Platelets/cytology
  • Humans
  • Iridium/chemistry
  • Adenosine Triphosphate/metabolism
  • Organometallic Compounds/chemistry
  • Phospholipase C gamma/metabolism
  • Platelet Activation/drug effects
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/drug effects
  • Calcium/metabolism
  • Platelet Aggregation Inhibitors/chemistry
  • Protein Kinase C/metabolism

ASJC Scopus subject areas

  • Genetics

Cite this

Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation. / Shyu, Kou Gi; Velusamy, Marappan; Hsia, Chih Wei; Yang, Chih Hao; Hsia, Chih Hsuan; Chou, Duen Suey; Jayakumar, Thanasekaran; Sheu, Joen Rong; Li, Jiun Yi.

In: International Journal of Molecular Medicine, Vol. 41, No. 5, 01.05.2018, p. 2589-2600.

Research output: Contribution to journalArticle

Shyu, Kou Gi ; Velusamy, Marappan ; Hsia, Chih Wei ; Yang, Chih Hao ; Hsia, Chih Hsuan ; Chou, Duen Suey ; Jayakumar, Thanasekaran ; Sheu, Joen Rong ; Li, Jiun Yi. / Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation. In: International Journal of Molecular Medicine. 2018 ; Vol. 41, No. 5. pp. 2589-2600.
@article{86af6594e37d43c68c8fdee6bdc72109,
title = "Novel iridium (III)-derived organometallic compound for the inhibition of human platelet activation",
abstract = "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.",
keywords = "C-Jun N-terminal kinase 1, Ir (III)-derived complex, Phospholipase Cγ2-protein kinase C cascade, Platelet activation, Protein kinase B, P-Selectin/metabolism, Blood Platelets/cytology, Humans, Iridium/chemistry, Adenosine Triphosphate/metabolism, Organometallic Compounds/chemistry, Phospholipase C gamma/metabolism, Platelet Activation/drug effects, Proto-Oncogene Proteins c-akt/metabolism, Signal Transduction/drug effects, Calcium/metabolism, Platelet Aggregation Inhibitors/chemistry, Protein Kinase C/metabolism",
author = "Shyu, {Kou Gi} and Marappan Velusamy and Hsia, {Chih Wei} and Yang, {Chih Hao} and Hsia, {Chih Hsuan} and Chou, {Duen Suey} and Thanasekaran Jayakumar and Sheu, {Joen Rong} and Li, {Jiun Yi}",
year = "2018",
month = "5",
day = "1",
doi = "10.3892/ijmm.2018.3472",
language = "English",
volume = "41",
pages = "2589--2600",
journal = "International Journal of Molecular Medicine",
issn = "1107-3756",
publisher = "Spandidos Publications",
number = "5",

}

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

PY - 2018/5/1

Y1 - 2018/5/1

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

UR - http://www.scopus.com/inward/record.url?scp=85042798273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042798273&partnerID=8YFLogxK

U2 - 10.3892/ijmm.2018.3472

DO - 10.3892/ijmm.2018.3472

M3 - Article

C2 - 29436605

AN - SCOPUS:85042798273

VL - 41

SP - 2589

EP - 2600

JO - International Journal of Molecular Medicine

JF - International Journal of Molecular Medicine

SN - 1107-3756

IS - 5

ER -