Novel iridium (III)‑derived organometallic compound for the inhibition of human platelet activation Corrigendum in /10.3892/ijmm.2019.4177

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

doi:10.3892/ijmm.2018.3472

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

Corrigendum in: /10.3892/ijmm.2019.4177

Authors:
- 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
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Affiliations: Division of Cardiology, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111, Taiwan, R.O.C., Department of Chemistry, North Eastern Hill University, Shillong, Meghalaya 793022, India, Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
Published online on: February 7, 2018 https://doi.org/10.3892/ijmm.2018.3472
Pages: 2589-2600
Copyright: © Shyu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Jayakumar T, Yang CH, Geraldine P, Yen TL and Sheu JR: The pharmacodynamics of antiplatelet compounds in thrombosis treatment. Expert Opin Drug Metab Toxicol. 12:615–632. 2016. View Article : Google Scholar : PubMed/NCBI
2	Belloc C, Lu H, Soria C, Fridman R, Legrand Y and Menashi S: The effect of platelets on invasiveness and protease production of human mammary tumor cells. Int J Cancer. 60:413–417. 1995. View Article : Google Scholar : PubMed/NCBI
3	Felding-Habermann B, Ooole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, Hughes PE, Pampori N, Shattil SJ, Saven A, et al: Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA. 98:1853–1858. 2001. View Article : Google Scholar : PubMed/NCBI
4	Boucharaba A, Serre CM, Gres S, Saulnier-Blache JS, Bordet JC, Guglielmi J, Clezardin P and Peyruchaud O: Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest. 114:1714–1725. 2004. View Article : Google Scholar : PubMed/NCBI
5	Iavicoli I, Cufino V, Corbi M, Goracci M, Caredda E, Cittadini A, Bergamaschi A and Sgambato A: Rhodium and iridium salts inhibit proliferation and induce DNA damage in rat fibroblasts in vitro. Toxicol In Vitro. 26:963–969. 2012. View Article : Google Scholar : PubMed/NCBI
6	Iavicoli I, Fontana L, Marinaccio A, Alimonti A, Pino A, Bergamaschi A and Calabrese EJ: The effects of iridium on the renal function of female wistar rats. Ecotoxicol Environ Safe. 74:1795–1799. 2011. View Article : Google Scholar
7	Romero-Canelón I and Sadler PJ: Next-generation metal anticancer complexes: Multitargeting via redox modulation. Inorg Chem. 52:12276–12291. 2013. View Article : Google Scholar : PubMed/NCBI
8	Yellol J, Pérez SA, Buceta A, Yellol G, Donaire A, Szumlas P, Bednarski PJ, Makhloufi G, Janiak C, Espinosa A and Ruiz J: Novel C, N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes as antitumor and antiangiogenic agents: A structure-activity relationship study. J Med Chem. 58:7310–7327. 2015. View Article : Google Scholar : PubMed/NCBI
9	Schmitt F, Donnelly K, Muenzner JK, Rehm T, Novohradsky V, Brabec V, Kasparkova J, Albrecht M, Schobert R and Mueller T: Effects of histidin-2-ylidene vs. imidazol-2-ylidene ligands on the anticancer and antivascular activity of complexes of ruthenium, iridium, platinum, and gold. J Inorg Biochem. 163:221–228. 2016. View Article : Google Scholar : PubMed/NCBI
10	Sheu JR, Lee CR, Lin CH, Hsiao G, Ko WC, Chen YC and Yen MH: Mechanisms involved in the antiplatelet activity of staphylococcus aureus lipoteichoic acid in human platelets. Thromb Haemost. 83:777–784. 2000.PubMed/NCBI
11	Chou DS, Hsiao G, Shen MY, Tsai YJ, Chen TF and Sheu JR: ESR spin trapping of a carbon-centered free radical from agonist-stimulated human platelets. Free Radic Biol Med. 39:237–248. 2005. View Article : Google Scholar : PubMed/NCBI
12	Harrison P and Cramer EM: Platelet alpha-granules. Blood Rev. 7:52–62. 1993. View Article : Google Scholar : PubMed/NCBI
13	Singer WD, Brown HA and Sternweis PC: Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. Annu Rev Biochem. 66:475–509. 1997. View Article : Google Scholar : PubMed/NCBI
14	Woulfe DS: Akt signaling in platelet and thrombosis. Expert Rev Hematol. 3:81–91. 2010. View Article : Google Scholar : PubMed/NCBI
15	Roux PP and Blenis J: ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 68:320–344. 2004. View Article : Google Scholar : PubMed/NCBI
16	Bugaud F, Nadal-Wollbold F, Levy-Toledano S, Rosa JP and Bryckaert M: Regulation of c-jun-NH2 terminal kinase and extracellular-signal regulated kinase in human platelets. Blood. 94:3800–3805. 1999.PubMed/NCBI
17	Lip GY: Chin BS and Blann A: Cancer and the prothrombotic state. Lancet Oncol. 3:27–34. 2002. View Article : Google Scholar : PubMed/NCBI
18	Ferroni P, Della-Morte D, Palmirotta R, McClendon M, Testa G, Abete P, Rengo F, Rundex T, Guadagni F and Roselli M: Platinum-based compounds and risk for cardiovascular toxicity in the elderly: Role of the antioxidants in chemoprevention. Rejuvenation Res. 14:293–308. 2011. View Article : Google Scholar : PubMed/NCBI
19	Jafri M and Protheroe A: Cisplatin-associated thrombosis. Anticancer Drugs. 19:927–929. 2008. View Article : Google Scholar : PubMed/NCBI
20	Barni S, Labianca R, Agnelli G, Bonizzoni E, Verso M, Mandalà M, Brighenti M, Petrelli F, Bianchini C, Perrone T and Gasparini G: Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: Results of a retrospective analysis of the PROTECHT study. J Transl Med. 20(179)2011.
21	Dasanu CA: Gemcitabine: Vascular toxicity and prothrombotic potential. Expert Opin Drug Safe. 7:703–716. 2008. View Article : Google Scholar
22	Kaibuchi K, Sano K, Hoshijima M, Takai Y and Nishizuka Y: Phosphatidylinositol turnover in platelet activation; calcium mobilization and protein phosphorylation. Cell Calcium. 3:323–335. 1982. View Article : Google Scholar : PubMed/NCBI
23	Ragab A, Séverin S, Gratacap MP, Aguado E, Malissen M, Jandrot-Perrus M, Malissen B, Ragab-Thomas J and Payrastre B: Roles of the C-terminal tyrosine residues of LAT in GP VI-induced platelet activation: Insights into the mechanism of PLC gamma 2 activation. Blood. 110:2466–2474. 2007. View Article : Google Scholar : PubMed/NCBI
24	Walter U, Eigenthaler M, Geiger J and Reinhard M: Role of cyclic nucleotide-dependent protein kinases and their common substrate VASP in the regulation of human platelets. Adv Exp Med Biol. 344:237–249. 1993. View Article : Google Scholar : PubMed/NCBI
25	Chen J, De S, Damron DS, Chen WS, Hay N and Byzova TV: Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice. Blood. 104:1703–1710. 2004. View Article : Google Scholar : PubMed/NCBI
26	Chang L and Karin M: Mammalian MAP kinase signaling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
27	Adam F, Kauskot A, Rosa JP and Bryckaert M: Mitogen-activated protein kinases in hemostasis and thrombosis. J Thromb Haemost. 6:2007–2016. 2008. View Article : Google Scholar : PubMed/NCBI
28	Canobbio I, Reineri S, Sinigaglia F, Balduini C and Torti M: A role for p38 MAP kinase in platelet activation by von Willebrand factor. Thromb Haemost. 91:102–110. 2004.
29	Adam F, Kauskot A, Nurden P, Sulpice E, Hoylaerts MF, Davis RJ, Rosa JP and Bryckaert M: Platelet JNK1 is involved in secretion and thrombus formation. Blood. 115:4083–4092. 2010. View Article : Google Scholar : PubMed/NCBI
30	Wachowicz B, Olas B, Zbikowska HM and Buczyński A: Generation of reactive oxygen species in blood platelets. Platelets. 13:175–182. 2002. View Article : Google Scholar : PubMed/NCBI
31	Iavicoli I, Fontana L, Bergamaschi A, Conti ME, Pino A, Mattei D, Bocca B and Alimonti A: Sub-chronic oral exposure to iridium (III) chloride hydrate in female wistar rats: Distribution and excretion of the metal. Dose-Response. 10:405–414. 2012. View Article : Google Scholar : PubMed/NCBI