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Lipophilic statins inhibit growth and reduce invasiveness of human endometrial stromal cells

  • Anna Sokalska
  • Amanda B. Hawkins
  • Toshia Yamaguchi
  • Antoni J. DulebaEmail author
Reproductive Physiology and Disease
  • 51 Downloads

Abstract

Purpose

To compare effects of lipid-soluble statins (simvastatin, lovastatin, atorvastatin) and water-soluble statin (pravastatin) on growth and invasiveness of human endometrial stromal (HES) cells.

Methods

Endometrial biopsies were collected during the proliferative phase from five volunteers. HES cells were isolated and cultured in the absence or in the presence of simvastatin, lovastatin, atorvastatin, and pravastatin. Effects of statins on DNA synthesis, cell viability, activity of caspases 3/7 and invasiveness were evaluated.

Results

The proliferation of HES cells was significantly decreased by simvastatin (by 47–89%), lovastatin (by 46–78%), and atorvastatin (by 21–48%) in a concentration-dependent manner. Activity of executioner caspases 3/7 was significantly increased by simvastatin (by 10–25%), lovastatin (by 19%) and atorvastatin (by 7–10%) in a concentration-dependent manner. The greatest effects were observed in response to simvastatin. Accounting for the effects of statins on cell number, the invasiveness of HES cells was significantly decreased in cells treated with simvastatin (by 49%), lovastatin (by 54%), and atorvastatin (by 53%). Pravastatin had little or no effects on any of the tested endpoints.

Conclusions

Present findings demonstrate that only lipid-soluble among tested statins were effective in inhibition of growth and invasiveness of HES cells. These findings may have clinical relevance in treatment of endometriosis.

Keywords

Statins Lipophilic Hydrophilic Endometrial stroma Endometriosis 

Notes

Funding

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant U54 HD052668.

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177–200.  https://doi.org/10.1016/j.bpobgyn.2004.01.007.CrossRefPubMedGoogle Scholar
  2. 2.
    Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum Reprod Update. 2014;20(5):702–16.  https://doi.org/10.1093/humupd/dmu015.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mohammed H, D’Santos C, Serandour AA, Ali HR, Brown GD, Atkins A, et al. Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell Rep. 2013;3(2):342–9.  https://doi.org/10.1016/j.celrep.2013.01.010.CrossRefPubMedGoogle Scholar
  4. 4.
    Candiani GB, Fedele L, Vercellini P, Bianchi S, Di Nola G. Repetitive conservative surgery for recurrence of endometriosis. Obstet Gynecol. 1991;77(3):421–4.PubMedGoogle Scholar
  5. 5.
    Bruner-Tran KL, Osteen KG, Duleba AJ. Simvastatin protects against the development of endometriosis in a nude mouse model. J Clin Endocrinol Metab. 2009;94(7):2489–94.  https://doi.org/10.1210/jc.2008-2802.CrossRefPubMedGoogle Scholar
  6. 6.
    Oktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB. High-dose atorvastatin causes regression of endometriotic implants: a rat model. Human Reprod. 2007;22(5):1474–80.  https://doi.org/10.1093/humrep/del505.CrossRefGoogle Scholar
  7. 7.
    Sharma I, Dhawan V, Mahajan N, Saha SC, Dhaliwal LK. In vitro effects of atorvastatin on lipopolysaccharide-induced gene expression in endometriotic stromal cells. Fertil Steril. 2010;94(5):1639–46.e1.  https://doi.org/10.1016/j.fertnstert.2009.10.003.CrossRefPubMedGoogle Scholar
  8. 8.
    Yilmaz B, Ozat M, Kilic S, Gungor T, Aksoy Y, Lordlar N, et al. Atorvastatin causes regression of endometriotic implants in a rat model. Reprod Biomed Online. 2010;20(2):291–9.  https://doi.org/10.1016/j.rbmo.2009.11.004.CrossRefPubMedGoogle Scholar
  9. 9.
    Taylor HS, Alderman Iii M, D’Hooghe TM, Fazleabas AT, Duleba AJ. Effect of simvastatin on baboon endometriosis. Biol Reprod. 2017;97(1):32–8.  https://doi.org/10.1093/biolre/iox058.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther. 2000;294(3):1043–6.PubMedGoogle Scholar
  11. 11.
    Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003;108(4):426–31.CrossRefGoogle Scholar
  12. 12.
    Dje N’Guessan P, Riediger F, Vardarova K, Scharf S, Eitel J, Opitz B, et al. Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29(3):380–6.  https://doi.org/10.1161/ATVBAHA.108.178319.CrossRefPubMedGoogle Scholar
  13. 13.
    Kyama CM, Overbergh L, Debrock S, Valckx D, Vander Perre S, Meuleman C, et al. Increased peritoneal and endometrial gene expression of biologically relevant cytokines and growth factors during the menstrual phase in women with endometriosis. Fertil Steril. 2006;85(6):1667–75.  https://doi.org/10.1016/j.fertnstert.2005.11.060.CrossRefPubMedGoogle Scholar
  14. 14.
    Chung HW, Lee JY, Moon HS, Hur SE, Park MH, Wen Y, et al. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril. 2002;78(4):787–95.CrossRefGoogle Scholar
  15. 15.
    Piotrowski PC, Kwintkiewicz J, Rzepczynska IJ, Seval Y, Cakmak H, Arici A, et al. Statins inhibit growth of human endometrial stromal cells independently of cholesterol availability. Biol Reprod. 2006;75:107–11.CrossRefGoogle Scholar
  16. 16.
    Sokalska A, Wong DH, Cress A, Piotrowski PC, Rzepczynska I, Villanueva J, et al. Simvastatin induces apoptosis and alters cytoskeleton in endometrial stromal cells. J Clin Endocrinol Metab. 2010;95(7):3453–9.  https://doi.org/10.1210/jc.2010-0072.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sokalska A, Cress A, Bruner-Tran KL, Osteen KG, Taylor HS, Ortega I, et al. Simvastatin decreases invasiveness of human endometrial stromal cells. Biol Reprod. 2012;87:1–6.  https://doi.org/10.1095/biolreprod.111.098806.CrossRefGoogle Scholar
  18. 18.
    Sokalska A, Anderson M, Villanueva J, Ortega I, Bruner-Tran KL, Osteen KG, et al. Effects of simvastatin on retinoic acid system in primary human endometrial stromal cells and in a chimeric model of human endometriosis. J Clin Endocrinol Metab. 2013;98:E463–71.  https://doi.org/10.1210/jc.2012-3402.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cakmak H, Basar M, Seval-Celik Y, Osteen KG, Duleba AJ, Taylor HS, et al. Statins inhibit monocyte chemotactic protein 1 expression in endometriosis. Reprod Sci. 2012;19(6):572–9.  https://doi.org/10.1177/1933719111430998.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Esfandiari N, Khazaei M, Ai J, Bielecki R, Gotlieb L, Ryan E, et al. Effect of a statin on an in vitro model of endometriosis. Fertil Steril. 2007;87(2):257–62.CrossRefGoogle Scholar
  21. 21.
    Nasu K, Yuge A, Tsuno A, Narahara H. Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis. Fertil Steril. 2009;92(6):2097–9.  https://doi.org/10.1016/j.fertnstert.2009.06.055.CrossRefPubMedGoogle Scholar
  22. 22.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–30.  https://doi.org/10.1038/343425a0.CrossRefPubMedGoogle Scholar
  23. 23.
    Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins. Int J Cardiol. 2003;90(2–3):317–21.CrossRefGoogle Scholar
  24. 24.
    Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–8.  https://doi.org/10.1056/NEJMoa042378.CrossRefPubMedGoogle Scholar
  25. 25.
    Schweitzer M, Mitmaker B, Obrand D, Sheiner N, Abraham C, Dostanic S, et al. Atorvastatin modulates matrix metalloproteinase expression, activity, and signaling in abdominal aortic aneurysms. Vasc Endovasc Surg. 2010;44(2):116–22.  https://doi.org/10.1177/1538574409348352.CrossRefGoogle Scholar
  26. 26.
    Porter KE, Naik J, Turner NA, Dickinson T, Thompson MM, London NJ. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vasc Surg. 2002;36(1):150–7.CrossRefGoogle Scholar
  27. 27.
    Ali OF, Growcott EJ, Butrous GS, Wharton J. Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells. Respir Res. 2011;12:137.  https://doi.org/10.1186/1465-9921-12-137.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bedi O, Dhawan V, Sharma PL, Kumar P. Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn Schmiedeberg’s Arch Pharmacol. 2016;389(7):695–712.  https://doi.org/10.1007/s00210-016-1252-4.CrossRefGoogle Scholar
  29. 29.
    Fong CW. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem. 2014;85:661–74.  https://doi.org/10.1016/j.ejmech.2014.08.037.CrossRefPubMedGoogle Scholar
  30. 30.
    Abe M, Toyohara T, Ishii A, Suzuki T, Noguchi N, Akiyama Y, et al. The HMG-CoA reductase inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides. Drug Metab Pharmacokinet. 2010;25(3):274–82.CrossRefGoogle Scholar
  31. 31.
    Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998;19(1):26–37.CrossRefGoogle Scholar
  32. 32.
    Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117–25.  https://doi.org/10.1111/j.1472-8206.2004.00299.x.CrossRefPubMedGoogle Scholar
  33. 33.
    Corpataux JM, Naik J, Porter KE, London NJ. The effect of six different statins on the proliferation, migration, and invasion of human smooth muscle cells. J Surg Res. 2005;129(1):52–6.  https://doi.org/10.1016/j.jss.2005.05.016.CrossRefPubMedGoogle Scholar
  34. 34.
    Nègre-Aminou P, van Vliet AK, van Erck M, van Thiel GC, van Leeuwen RE, Cohen LH. Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types. Biochim Biophys Acta. 1997;1345(3):259–68.CrossRefGoogle Scholar
  35. 35.
    Turner NA, Midgley L, O’Regan DJ, Porter KE. Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion. J Cardiovasc Pharmacol. 2007;50(4):458–61.  https://doi.org/10.1097/FJC.0b013e318123767f.CrossRefPubMedGoogle Scholar
  36. 36.
    Chuang SC, Liao HJ, Li CJ, Wang GJ, Chang JK, Ho ML. Simvastatin enhances human osteoblast proliferation involved in mitochondrial energy generation. Eur J Pharmacol. 2013;714(1–3):74–82.  https://doi.org/10.1016/j.ejphar.2013.05.044.CrossRefPubMedGoogle Scholar
  37. 37.
    Xia S, Kang J, Jiang Y, Huang D, Wang S, Pang B. Simvastatin promotes alveolar epithelial cell proliferation and attenuates cigarette smokeinduced emphysema in rats. Mol Med Rep. 2015;12(4):5903–10.  https://doi.org/10.3892/mmr.2015.4172.CrossRefPubMedGoogle Scholar
  38. 38.
    Almassinokiani F, Mehdizadeh A, Sariri E, Rezaei M, Almasi A, Akbari H, et al. Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis. Med Sci Monit. 2013;19:534–9.  https://doi.org/10.12659/MSM.883967.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Anna Sokalska
    • 1
  • Amanda B. Hawkins
    • 2
  • Toshia Yamaguchi
    • 3
  • Antoni J. Duleba
    • 4
    Email author
  1. 1.Department of Obstetrics and GynecologyUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Obstetrics and GynecologyUniversity of California DavisSacramentoUSA
  3. 3.Department of PsychiatryUniversity of California RiversideRiversideUSA
  4. 4.Division of Reproductive Endocrinology and Infertility, Department of Reproductive MedicineUniversity of California San DiegoLa JollaUSA

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