Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen

Manasa K. Nayak; Sunil K. Singh; Arnab Roy; Vivek Prakash; Anand Kumar; Debabrata Dash

doi:10.1160/TH11-03-0178

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 106(04): 624-635
DOI: 10.1160/TH11-03-0178

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen

Manasa K. Nayak

¹Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

,

Sunil K. Singh

¹Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

,

Arnab Roy

¹Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

,

Vivek Prakash

²Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

,

Anand Kumar

²Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

,

Debabrata Dash

¹Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

› Institutsangaben

Abstract

Summary

Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated in detail. In the present report we show that tamoxifen is endowed with significant inhibitory property against human platelet aggregation. From a series of in vivo and in vitro studies tamoxifen was found to inhibit almost all platelet functions, prolong tail bleeding time in mouse and profoundly prevent thrombus formation at injured arterial wall in mice, as well as on collagen matrix perfused with platelet-rich plasma under arterial shear against the vehicle dimethylsulfoxide (DMSO). These findings strongly suggest that tamoxifen significantly downregulates platelet responses and holds potential as a promising anti-platelet / anti-thrombotic agent.

Keywords

Antiplatelet drug - estrogen receptor - platelet aggregation - selective estrogen receptor modulators (SERM) - thrombosis

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Referenzen

References
1 MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998; 50: 151-196.
2 Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003; 2: 205-213.
3 Wiseman H, Paganga G, Rice-Evans C. et al. Protective actions of tamoxifen and 4-hydroxytamoxifen against oxidative damage to human low-density lipoproteins: a mechanism accounting for the cardioprotective action of tamoxifen. Biochem J 1993; 292: 635-638.
4 Medina PD, Payre BL, Bernad J. et al. Tamoxifen is a potent inhibitor of cholesterol esterification and prevents the formation of foam cells. J Pharmacol Exp Ther 2004; 308: 1165-1173.
5 Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-205.
6 Grainger DJ, Metcalfe JC. Tamoxifen: teaching an old drug new tricks?. Nat Med 1996; 2: 381-385.
7 Park WC, Jordan VC. Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention. Trends Mol Med 2002; 8: 82-88.
8 Jordan VC. The only true antiestrogen is no estrogen. Mol Cell Endocrinol 1990; 74: C91-C95.
9 Wiseman H. Tamoxifen as an antioxidant and cardioprotectant. Biochem Soc Symp 1995; 61: 209-219.
10 Stocker R, Keaney JFJ.. Role of oxidative modifications in atherosclerosis. Physiol Rev 2004; 84: 1381-1478.
11 Zarate CAJ, Singh JB, Carlson PJ. et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 2007; 9: 561-570.
12 Couldwell WT, Hinton DR, Surnock AA. et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 1996; 2: 619-622.
13 Robins HI, Won M, Seiferheld WF. et al. Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021. Neuro Onco 2006; 8: 47-52.
14 Mastronardi L, Puzzilli F, Ruggeri A. Tamoxifen as a potential treatment of glioma. Anticancer Drugs 1998; 9: 581-586.
15 Subramaniam M, Frenette PS, Saffaripour S. et al. Defects in hemostasis in P-selectin-deficient mice. Blood 1996; 87: 1238-1242.
16 Denis C, Methia N, Frenette PS. et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 1998; 95: 9524-9529.
17 Vollmar B, Schmits R, Kunz D. et al. Lack of in vivo function of CD31 in vascular thrombosis. Thromb Haemost 2001; 85: 160-164.
18 Chang Y, Lee JJ, Chen WF. et al. A novel role for tamoxifen in the inhibition of human platelets. Transl Res 2011; 157: 81-91.
19 Grey AB, Evans MC, Kyle C. et al. The anti-oestrogen tamoxifen produces haemodilution in normal postmenopausal women. J Intern Med 1997; 242: 383-388.
20 Vitseva O, Flockhart DA, Jin Y. et al. The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates. J Pharmacol Exp Ther 2005; 312: 1144-1150.
21 Nayak M K, Kumar K, Dash D. Regulation of proteasome activity in activated human platelets. Cell Calcium 2011; 49: 228-232.
22 Shrivastava S, Bera T, Singh S K. et al. Characterization of novel anti-platelet properties of silver nanoparticles. ACS Nano 2009; 3: 1357-1364.
23 Jeske WP, Walenga JM, Szatkowski E. et al. Effect of glycoprotein IIb/IIIa antagonists on the HIT seruminduced activation of platelets. Thromb Res 1997; 88: 271-281.
24 Shankey TV, Jeske WP, Walenga JM. Flow cytometric analysis of platelets and platelet function. In: Immunophenotyping Wiley. New York: 2000: 333-359.
25 Dash D, Rao GRK. et al. Characterization of the effects of propranolol on the physical state of platelet membrane. Arch Biochem Biophys 1990; 276: 343-347.
26 May F, Hagedorn I, Pleines I. et al. CLEC-2 is an essential platelet activating receptor in hemostasis and thrombosis. Blood 2009; 114: 3464-3472.
27 Flaumenhaft R, Dilks JR, Rozenvayn R. et al. The actin cytoskeleton differentially regulates platelet a-granule and dense-granule secretion. Blood 2005; 105: 3879-3887.
28 Dvorak AM. Monograph: Procedural guide to specimen handling for the ultra-structural pathology service laboratory. J Electron Microsc Technol 1987; 6: 255-301.
29 Lee KH, Ward BA, Desta Z. et al. Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 791: 245-253.
30 Dobrydneva Y, Weatherman RV, Trebley JP. et al. Tamoxifen stimulates calcium entry into human Platelets. J Cardiovasc Pharmacol 2007; 50: 380-390.
31 Shattil SJ, Hoxie JA, Cunningham M. et al. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107-11114.
32 Hantgan RR, Taylor RG, Lewis JC. Platelets interact with fibrin only after activation. Blood 1985; 65: 1299-1311.
33 Ono A, Westein E, Hsiao S. et al. Identification of a fibrin independent platelet contractile mechanism regulating primary hemostasis and thrombous growth. Blood 2008; 112: 90-99.
34 Litvinov RI, Nagaswami C, Vilaire G. et al. Functional and strucural correlations of individual α_IIbβ₃ molecules. Blood 2004; 104: 3979-3985.
35 Khetawath G, Faraday N, Nealen ML. et al. Human megakaryocytes and platelets contain the estrogen receptor β and androgen receptor (AR): testosterone regulates AR expression. Blood 2000; 95: 2289-2296.
36 Jayachandran M, Miller VM. Human platelets contain estrogen receptor a, caveolin-1 and estrogen receptor associated proteins. Platelets 2003; 14: 75-81.
37 Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discovery 2004; 3: 950-964.
38 Pettersson K, Delaunay F, Gustafsson JA. Estrogen receptor beta acts as a dominant regulator of estrogen. Oncogene 2000; 43: 4970-4978.
39 Hall JM, McDonnell DP. The estrogen receptor beta isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999; 140: 5566-5578.
40 Kushner PJ, Agard D, Feng WJ. et al. Oestrogen receptor function at classical and alternative response elements. Novartis Found Symp 2000; 230: 20-26.
41 Migliaccio A, Castoria G, Di Domenico M. et al. Steroid-induced androgen receptoroestradiol receptor β-Src complex triggers prostate cancer cell proliferation. EMBO J 2000; 19: 5406-5417.
42 Lu Q, Pallas DC, Surks HK. et al. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor a. Proc Natl Acad Sci USA 2004; 101: 17126-17131.
43 Leng X, Zhang W, Nieswandt B. et al. Effects of estrogen replacement therapies on mouse platelet function and glycoprotein VI levels. Circ Res 2005; 97: 415-417.
44 Moro L, Reineri S, Piranda D. et al. Nongenomic effects of 17β estradiol in human platelets: potentiation of thrombin-induced aggregation through estrogen receptor β and Src kinase. Blood 2005; 105: 115-121.
45 Kansra S, Yamagata S, Sneade L. et al. Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol 2005; 239: 27-36.
46 Lam L, Hu X, Aktary Z. et al. Tamoxifen and ICI 182,780 increase Bcl-2 levels and inhibit growth of breast carcinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independent of ERa. Breast Cancer Res Treat 2009; 118: 605-621.
47 Merciera I, Maderc S, Calderone A. Tamoxifen and ICI 182,780 negatively influenced cardiac cell growth via an estrogen receptor-independent mechanism. Cardiovasc Res 2003; 59: 883-892.
48 Gagliardi A, Collins DC. Inhibition of angiogenesis by antiestrogens. Cancer Res 1993; 53: 533-535.
49 MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998; 50: 151-196.
50 Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003; 2: 205-213.
51 Grainger DJ, Peter MS. Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence. Circulation 2005; 112: 3018-3024.
52 Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62: 315-320
53 Braithwaite RS, Chlebowski RT, Lau J. et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003; 18: 937-947.
54 Goldhaber SZ. Tamoxifen: preventing breast cancer and placing the risk of deep vein thrombosis in perspective. Circulation 2005; 111: 539-541.
55 Weitz IC, Israel VK, Liebman HA. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 1997; 79: 2024-2027.
56 Lopes MC, Vale MG, Carvalho A P.. Ca²⁺-dependent Binding of Tamoxifen to Calmodulin Isolated from Bovine Brain. Cancer Res 1990; 50: 2753-2758.
57 O’Brien CA, Liskamp RM, Soloman DH. et al. Triphenylenes: a new class of protein kinase C inhibitors. J Natl Cancer 1986; 76: 1243-1246.
58 Kiss Z. Tamoxifen stimulates phospholipase D activity by an estrogen receptor-independent mechanism. FEBS Lett 1994; 355: 173-177.
59 Kedjouar B, de Medina P, Oulad-Abdelghani M. et al. Molecular characterization of the microsomal tamoxifen binding Site. J Biol Chem 2004; 279: 34048-34061.
60 Jan CR, An-Jen C, Chang HT. et al. The anti-breast cancer drug tamoxifen alters Ca²⁺ movement in Chinese hamster ovary (CHO-K1) cells. Arch Toxicol 2003; 7: 160-166.
61 Lu YC, Jiann BP, Chang HT. et al. Effect of the anti-breast cancer drug tamoxifen on Ca²⁺ movement in human osteosarcoma cells. Pharmacol Toxicol 2002; 91: 34-39.
62 Zamaraeva M, Charishnikova O, Saidkhodjaev A. et al. Calcium mobilization by the plant estrogen ferutinin does not induce blood platelet aggregation. Pharmacol Rep 2010; 62: 1117-1126.
63 Lam HYP.. Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Commun 1984; 118: 27-32.
64 McClay EF, McClay MT, Monroe L. et al. A Phase II study of high dose tamoxifen and weekly cisplatin in patients with metastatic melanoma. Melanoma Res 2001; 11: 309-313.
65 Bashey A, Corringham S, Garrett J. et al. A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle. Bone Marrow Transplant 2000; 25: 519-524.
66 Trump D L, Smith DC, Ellis PG. et al. High-dose oral tamoxifen, a potential multi-drug-resistance–reversal agent: Phase I trial in combination with vinblastine. J Natl Cancer Inst 1992; 84: 1811-1816.
67 Choi JS, Kang KW. Enhanced tamoxifen bioavailability after oral administration of tamoxifen in rats pretreated with naringin. Arch Pharm Res 2008; 31: 1631-1636.
68 Yao JC, Thomakos N, McLaughlin P. et al. Tamoxifen-induced thrombocytopenia. Am J Clin Oncol 1999; 22: 529-532.
69 Colditz GA, Willett WC, Stampfer JJ. et al. Menopause and the risk for coronary heart disease in women. N Engl J Med 1987; 316: 1105-1110.