Khamrang Themmila, Hung Kuo-Chen, Hsia Chih-Hsuan, Hsieh Cheng-Ying, Velusamy Marappan, Jayakumar Thanasekaran, Sheu Joen-Rong
Department of Chemistry, North Eastern Hill University, Shillong 793022, India.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Int J Mol Sci. 2017 Apr 27;18(5):916. doi: 10.3390/ijms18050916.
In oncotherapy, ruthenium complexes are considered as potential alternatives for platinum compounds, and have been proved as promising anticancer drugs with high efficacy and lesser side effects. Platelet activation plays a major role in cancer metastasis and progression. Hence, this study explored the effect of a newly synthesized ruthenium complex, [Ru(η⁶-cymene)(L)Cl]BF₄(TQ5), where L = 4-phenyl-2-pyridin-2-yl-quinazoline), on human platelet activation. TQ5 (3-5 µM) inhibited concentration-dependent collagen-induced platelet aggregation in washed human platelets. However, this compound only inhibited platelet aggregation at a maximum concentration of 500 and 100 µM against thrombin and 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin (U46619)-induced stimulation, respectively. TQ5 inhibited collagen-induced ATP release and calcium mobilization ([Ca]), without inducing cell cytotoxicity. In addition, neither SQ22536, an adenylate cyclase inhibitor, nor 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, significantly reversed the TQ5-mediated inhibition of platelet aggregation. TQ5 inhibited the collagen-induced phosphorylation of protein kinase B (Akt) and c-Jun N-terminal kinase (JNK), but did not effectively inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) and p38-mitogen-activated protein kinase (p38-MAPK) in human platelets. Additionally, TQ5 significantly prolonged the closure time in whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. This study demonstrates, for the first time, that a newly synthesized ruthenium complex, TQ5, exhibits potent antiplatelet activity by hindering ATP release and [Ca], and by decreasing the activation of Akt/JNK signals. Together, these results suggest that TQ5 could be developed as a therapeutic agent that helps prevent or treat thromboembolic disorders, since it is found to be potently more effective than a well-established antithrombotic aspirin.
在肿瘤治疗中，钌配合物被视为铂类化合物的潜在替代品，并且已被证明是有前景的抗癌药物，具有高效和低副作用的特点。血小板活化在癌症转移和进展中起主要作用。因此，本研究探讨了一种新合成的钌配合物[Ru(η⁶-对异丙基苯)(L)Cl]BF₄（TQ5，其中L = 4-苯基-2-吡啶-2-基喹唑啉）对人血小板活化的影响。TQ5（3 - 5 μM）在洗涤后的人血小板中浓度依赖性地抑制胶原诱导的血小板聚集。然而，该化合物分别在最大浓度为500 μM和100 μM时才抑制凝血酶和9,11-二脱氧-11α,9α-环氧甲撑前列腺素（U46619）诱导的刺激所引起的血小板聚集。TQ5抑制胶原诱导的ATP释放和钙动员（[Ca]），且不诱导细胞毒性。此外，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（ODQ）均未显著逆转TQ5介导的血小板聚集抑制作用。TQ5抑制胶原诱导的蛋白激酶B（Akt）和c-Jun氨基末端激酶（JNK）的磷酸化，但未有效抑制人血小板中的细胞外信号调节激酶1/2（ERK1/2）和p38-丝裂原活化蛋白激酶（p38-MAPK）。此外，TQ5显著延长全血中的闭合时间，并增加小鼠血栓性血小板栓形成的闭塞时间。本研究首次证明，新合成的钌配合物TQ5通过阻碍ATP释放和[Ca]以及降低Akt/JNK信号的激活而表现出强大的抗血小板活性。总之，这些结果表明TQ5可被开发为一种有助于预防或治疗血栓栓塞性疾病的治疗剂，因为它被发现比成熟的抗血栓药物阿司匹林更有效。
