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.