Shyu Ren-Shi, Khamrang Themmila, Sheu Joen-Rong, Hsia Chih-Wei, Velusamy Marappan, Hsia Chih-Hsuan, Chou Duen-Suey, Chang Chao-Chien
Division of Nephrology, Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan 330, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Bioinorg Chem Appl. 2018 May 2;2018:8291393. doi: 10.1155/2018/8291393. eCollection 2018.
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]BF 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 Ca mobilization, P-selectin expression, and the phosphorylation of phospholipase C2 (PLC2), 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 PLC2-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.
据报道，血小板活化在动脉血栓形成、癌症转移和进展中起主要作用。最近，我们开发了一种新型的基于铱（III）的化合物，[Ir（Cp）1-（2-吡啶基）-3-（4-二甲基氨基苯基）咪唑并[1,5-a]吡啶 Cl]BF 或 Ir-6，并评估了其作为抗血小板药物的有效性。Ir-6 对胶原蛋白刺激的人血小板聚集表现出更高的效力。Ir-6 还抑制了胶原蛋白激活的血小板中的 ATP 释放、细胞内钙动员、P-选择素表达以及磷脂酶 C2（PLC2）、蛋白激酶 C（PKC）、v-Akt 鼠胸腺瘤病毒癌基因（Akt）/蛋白激酶 B 和丝裂原活化蛋白激酶（MAPK）的磷酸化。腺苷酸环化酶抑制剂 SQ22536 和鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮均未显著逆转 Ir-6 介导的对胶原蛋白诱导的血小板聚集的抑制作用。此外，Ir-6 在胶原蛋白激活的血小板或芬顿反应溶液中并未显著降低羟基自由基信号。在 2mg/kg 时，Ir-6 显著延长了实验小鼠的出血时间。总之，Ir-6 通过抑制信号通路（如 PLC2-PKC 级联反应以及随后对 Akt 和 MAPK 激活的抑制）来抑制血小板活化，从而最终抑制血小板聚集，发挥关键作用。因此，Ir-6 是预防或治疗血栓栓塞性疾病或破坏血小板与肿瘤细胞之间相互作用（这有助于肿瘤细胞生长和进展）的潜在治疗剂。
