Platelet activation has been reported to play a major role in arterial thrombosis, cancer metastasis, and progression. Recently, we developed a novel Ir(III)-based compound, [Ir(Cp∗)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]pyridine Cl]BF4 or Ir-6 and assessed its effectiveness as an antiplatelet drug. Ir-6 exhibited higher potency against human platelet aggregation stimulated by collagen. Ir-6 also inhibited ATP-release, intracellular Ca2+ mobilization, P-selectin expression, and the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), v-Akt murine thymoma viral oncogene (Akt)/protein kinase B, and mitogen-activated protein kinases (MAPKs), in collagen-activated platelets. 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-6-mediated inhibition of collagen-induced platelet aggregation. Moreover, Ir-6 did not considerably diminish OH radical signals in collagen-activated platelets or Fenton reaction solution. At 2 mg/kg, Ir-6 markedly prolonged the bleeding time in experimental mice. In conclusion, Ir-6 plays a crucial role by inhibiting platelet activation through the inhibition of signaling pathways, such as the PLCγ2-PKC cascade and the subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, Ir-6 is a potential therapeutic agent for preventing or treating thromboembolic disorders or disrupting the interplay between platelets and tumor cells, which contributes to tumor cell growth and progression.

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.

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.

Xanthohumol is the principal prenylated flavonoid in the hop plant (Humulus lupulus L.). Xanthohumol was found to be a very potent cancer chemopreventive agent through regulation of diverse mechanisms. However, no data are available concerning the effects of xanthohumol on platelet activation. The aim of this paper was to examine the antiplatelet effect of xanthohumol in washed human platelets. In the present paper, xanthohumol exhibited more-potent activity in inhibiting platelet aggregation stimulated by collagen. Xanthohumol inhibited platelet activation accompanied by relative [Ca(2+)](i) mobilization, thromboxane A(2) formation, hydroxyl radical (OH(●)) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Neither SQ22536, an inhibitor of adenylate cyclase, nor ODQ, an inhibitor of guanylate cyclase, reversed the xanthohumol-mediated inhibitory effect on platelet aggregation. Furthermore, xanthohumol did not significantly increase nitrate formation in platelets. This study demonstrates for the first time that xanthohumol possesses potent antiplatelet activity which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of the thromboxane A(2) formation, thereby leading to inhibition of [Ca(2+)](i) and finally inhibition of platelet aggregation. Therefore, this novel role of xanthohumol may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases.