Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2021 Feb 1;59(2):124–131. doi: 10.1007/s12275-021-0617-7

Raloxifene as a treatment option for viral infections

Subin Hong 1, JuOae Chang 1, Kwiwan Jeong 2,✉, Wonsik Lee 1,✉
PMCID: PMC7849956  PMID: 33527314

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene’s mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.

Keywords: raloxifene, drug repositioning, COVID-19, SARS-CoV-2, SERM, estrogen receptor

Acknowledgments

This work has been supported by Korea Disease Control and Prevention Agency (KCDC 2020-ER5329-00).

Footnotes

Conflict of Interest

We have no conflicts of interest to report.

Contributor Information

Kwiwan Jeong, Email: assylum@gbsa.or.kr.

Wonsik Lee, Email: wonsik.lee@skku.edu.

References

  1. Beral V, Million Women Study Collaborators Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427. doi: 10.1016/S0140-6736(03)14596-5. [DOI] [PubMed] [Google Scholar]
  2. Bryant HU, Glasebrook AL, Yang NN, Sato M. A pharmacological review of raloxifene. J. Bone Miner. Metab. 1996;14:1–9. doi: 10.1007/BF01771666. [DOI] [Google Scholar]
  3. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson JA, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–758. doi: 10.1038/39645. [DOI] [PubMed] [Google Scholar]
  4. Cappuccio FP, Siani A. Covid-19 and cardiovascular risk: Susceptibility to infection to SARS-CoV-2, severity and prognosis of Covid-19 and blockade of the renin-angiotensin-aldosterone system. An evidence-based viewpoint. Nutr. Metab. Cardiovasc. Dis. 2020;30:1227–1235. doi: 10.1016/j.numecd.2020.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clemett D, Spencer CM. Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000;60:379–411. doi: 10.2165/00003495-200060020-00013. [DOI] [PubMed] [Google Scholar]
  6. Coccolini F, Sartelli M, Kluger Y, Pikoulis E, Karamagioli E, Moore EE, Biffl WL, Peitzman A, Hecker A, Chirica M, et al. COVID-19 the showdown for mass casualty preparedness and management: the Cassandra Syndrome. World J. Emerg. Surg. 2020;15:26. doi: 10.1186/s13017-020-00304-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collaborative Group on Hormonal Factors in Breast Cancer Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394:1159–1168. doi: 10.1016/S0140-6736(19)31709-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281:2189–2197. doi: 10.1001/jama.281.23.2189. [DOI] [PubMed] [Google Scholar]
  9. Dariya B, Nagaraju GP. Understanding novel COVID-19: Its impact on organ failure and risk assessment for diabetic and cancer patients. Cytokine Growth Factor Rev. 2020;53:43–52. doi: 10.1016/j.cytogfr.2020.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N. Engl. J. Med. 1997;337:1641–1647. doi: 10.1056/NEJM199712043372301. [DOI] [PubMed] [Google Scholar]
  11. Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: Results from the MORE trial. Bone. 2003;33:522–532. doi: 10.1016/S8756-3282(03)00241-2. [DOI] [PubMed] [Google Scholar]
  12. DeMichele A, Troxel AB, Berlin JA, Weber AL, Bunin GR, Turzo E, Schinnar R, Burgh D, Berlin M, Rubin SC, et al. Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study. J. Clin. Oncol. 2008;26:4151–4159. doi: 10.1200/JCO.2007.14.0921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Di Martino V, Lebray P, Myers RP, Pannier E, Paradis V, Charlotte F, Moussalli J, Thabut D, Buffet C, Poynard T. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology. 2004;40:1426–1433. doi: 10.1002/hep.20463. [DOI] [PubMed] [Google Scholar]
  14. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637–645. doi: 10.1001/jama.282.7.637. [DOI] [PubMed] [Google Scholar]
  15. Evans GL, Bryant HU, Magee DE, Turner RT. Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology. 1996;137:4139–4144. doi: 10.1210/endo.137.10.8828469. [DOI] [PubMed] [Google Scholar]
  16. Fan H, Du X, Zhang J, Zheng H, Lu X, Wu Q, Li H, Wang H, Shi Y, Gao G, et al. Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium. Sci. Rep. 2017;7:41226. doi: 10.1038/srep41226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fugère P, Scheele WH, Shah A, Strack TR, Glant MD, Jolly E. Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in post-menopausal women. Am. J. Obstet. Gynecol. 2000;182:568–574. doi: 10.1067/mob.2000.104768. [DOI] [PubMed] [Google Scholar]
  18. Furusyo N, Ogawa E, Sudoh M, Murata M, Ihara T, Hayashi T, Ikezaki H, Hiramine S, Mukae H, Toyoda K, et al. Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: a randomized trial. J. Hepatol. 2012;57:1186–1192. doi: 10.1016/j.jhep.2012.08.003. [DOI] [PubMed] [Google Scholar]
  19. Gavriatopoulou M, Korompoki E, Fotiou D, Ntanasis-Stathopoulos I, Psaltopoulou T, Kastritis E, Terpos E, Dimopoulos MA. Organ-specific manifestations of COVID-19 infection. Clin. Exp. Med. 2020;20:493–506. doi: 10.1007/s10238-020-00648-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gianni W, Ricci A, Gazzaniga P, Brama M, Pietropaolo M, Votano S, Patanè F, Aglianò AM, Spera G, Marigliano V, et al. Raloxifene modulates interleukin-6 and tumor necrosis factor-α synthesis in vivo: results from a pilot clinical study. J. Clin. Endocrinol. Metab. 2004;89:6097–6099. doi: 10.1210/jc.2004-0795. [DOI] [PubMed] [Google Scholar]
  21. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet. Gynecol. 2000;95:95–103. doi: 10.1016/s0029-7844(99)00502-5. [DOI] [PubMed] [Google Scholar]
  22. Gottardis MM, Jordan VC. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987;47:4020–4024. [PubMed] [Google Scholar]
  23. Haldosén LA, Zhao C, Dahlman-Wright K. Estrogen receptor beta in breast cancer. Mol. Cell. Endocrinol. 2014;382:665–672. doi: 10.1016/j.mce.2013.08.005. [DOI] [PubMed] [Google Scholar]
  24. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M, et al. Estrogen receptors: how do they signal and what are their targets. Physiol. Rev. 2007;87:905–931. doi: 10.1152/physrev.00026.2006. [DOI] [PubMed] [Google Scholar]
  25. Hoenen T, Groseth A, Feldmann H. Therapeutic strategies to target the Ebola virus life cycle. Nat. Rev. Microbiol. 2019;17:593–606. doi: 10.1038/s41579-019-0233-2. [DOI] [PubMed] [Google Scholar]
  26. Jones, J.E., Le Sage, V., and Lakdawala, S.S. 2020. Viral and host heterogeneity and their effects on the viral life cycle. Nat. Rev. Microbiol.10.1038/s41579-020-00449-9. [DOI] [PMC free article] [PubMed]
  27. Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur. J. Cancer. 2008;44:30–38. doi: 10.1016/j.ejca.2007.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jordan RE, Adab P. Who is most likely to be infected with SARS-CoV-2? Lancet Infect. Dis. 2020;20:995–996. doi: 10.1016/S1473-3099(20)30395-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kesharwani D, Paliwal R, Satapathy T, Das Paul S. Rheumatiod arthritis: an updated overview of latest therapy and drug delivery. J. Pharmacopuncture. 2019;22:210–224. doi: 10.3831/KPI.2019.22.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kumar V, Chambon P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell. 1988;55:145–156. doi: 10.1016/0092-8674(88)90017-7. [DOI] [PubMed] [Google Scholar]
  31. Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, Singh R, Bhasin S, Jasuja R. The dynamic structure of the estrogen receptor. J. Amino Acids. 2011;2011:812540. doi: 10.4061/2011/812540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ledford H. Coronavirus breakthrough: Dexamethasone is first drug shown to save lives. Nature. 2020;582:469. doi: 10.1038/d41586-020-01824-5. [DOI] [PubMed] [Google Scholar]
  33. Levenson AS, Wolf DM, Catherino WH, Takei H, Jordan VC. Understanding the antiestrogenic actions of raloxifene and a mechanism of drug resistance to tamoxifen. Breast Cancer. 1998;5:99–106. doi: 10.1007/BF02966681. [DOI] [PubMed] [Google Scholar]
  34. Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. J. Natl. Cancer Inst. 1999;91:1809–1819. doi: 10.1093/jnci/91.21.1809. [DOI] [PubMed] [Google Scholar]
  35. Lo MK, Albariño CG, Perry JK, Chang S, Tchesnokov EP, Guerrero L, Chakrabarti A, Shrivastava-Ranjan P, Chatterjee P, McMullan LK, et al. Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases. Proc. Natl. Acad. Sci. USA. 2020;117:26946–26954. doi: 10.1073/pnas.2012294117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol. Rev. 1998;50:151–196. [PubMed] [Google Scholar]
  37. Mahase E. Covid-19: US approves remdesivir despite WHO trial showing lack of efficacy. BMJ. 2020;371:m4120. doi: 10.1136/bmj.m4120. [DOI] [Google Scholar]
  38. Matthay MA, Wick KD. Corticosteroids, COVID-19 pneumonia, and acute respiratory distress syndrome. J. Clin. Invest. 2020;130:6218–6221. doi: 10.1172/JCI143331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Myers L, Balakrishnan S, Reddy S, Gholamrezanezhad A. Coronavirus outbreak: is radiology ready? Mass casualty incident planning. J. Am. Coll. Radiol. 2020;17:724–729. doi: 10.1016/j.jacr.2020.03.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nelson HD. Menopause. Lancet. 2008;371:760–770. doi: 10.1016/S0140-6736(08)60346-3. [DOI] [PubMed] [Google Scholar]
  41. Omoto Y, Iwase H. Clinical significance of estrogen receptor β in breast and prostate cancer from biological aspects. Cancer Sci. 2015;106:337–343. doi: 10.1111/cas.12613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ozma MA, Maroufi P, Khodadadi E, Kose S, Esposito I, Ganbarov K, Dao S, Esposito S, Dal T, Zeinalzadeh E, et al. Clinical manifestation, diagnosis, prevention and control of SARS-CoV-2 (COVID-19) during the outbreak period. Infez. Med. 2020;28:153–165. [PubMed] [Google Scholar]
  43. Pardo J, Shukla AM, Chamarthi G, Gupte A. The journey of remdesivir: from Ebola to COVID-19. Drugs Context. 2020;9:2020–4. doi: 10.7573/dic.2020-4-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol. Ther. 2018;186:1–24. doi: 10.1016/j.pharmthera.2017.12.012. [DOI] [PubMed] [Google Scholar]
  45. Patel SK, Saikumar G, Rana J, Dhama J, Yatoo MI, Tiwari R, Rodriguez-Morales AJ, Dhama K. Dexamethasone: A boon for critically ill COVID-19 patients? Travel Med. Infect. Dis. 2020;37:101844. doi: 10.1016/j.tmaid.2020.101844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pawlak M, Lefebvre P, Staels B. General molecular biology and architecture of nuclear receptors. Curr. Top. Med. Chem. 2012;12:486–504. doi: 10.2174/156802612799436641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pearce ST, Jordan VC. The biological role of estrogen receptors a and β in cancer. Crit. Rev. Oncol. Hematol. 2004;50:3–22. doi: 10.1016/j.critrevonc.2003.09.003. [DOI] [PubMed] [Google Scholar]
  48. Peretz J, Hall OJ, Klein SL. Sex differences in influenza virus infection, vaccination, and therapies. In: Klein SL, Roberts CW, editors. Sex and Gender Differences in Infection and Treatments for Infectious Diseases. Cham, Switzerland: Springer International Publishing; 2015. pp. 183–210. [Google Scholar]
  49. Peretz J, Pekosz A, Lane AP, Klein SL. Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. Am. J. Physiol. Lung Cell. Mol. Physiol. 2016;310:L415–L425. doi: 10.1152/ajplung.00398.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752. doi: 10.1038/35021093. [DOI] [PubMed] [Google Scholar]
  51. Prasad A, Prasad M. Single virus targeting multiple organs: what we know and where we are heading? Front. Med. 2020;7:370. doi: 10.3389/fmed.2020.00370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ragia G, Manolopoulos VG. Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies. Eur. J. Clin. Pharmacol. 2020;76:1623–1630. doi: 10.1007/s00228-020-02963-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Rey JRC, Cervino EV, Rentero ML, Crespo EC, Álvaro AO, Casillas M. Raloxifene: mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice. Open Orthop. J. 2009;3:14–21. doi: 10.2174/1874325000903010014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids-new mechanisms for old drugs. N. Engl. J. Med. 2005;353:1711–1723. doi: 10.1056/NEJMra050541. [DOI] [PubMed] [Google Scholar]
  55. Riggs BL. The mechanisms of estrogen regulation of bone resorption. J. Clin. Invest. 2000;106:1203–1204. doi: 10.1172/JCI11468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators — mechanisms of action and application to clinical practice. N. Engl. J. Med. 2003;348:618–629. doi: 10.1056/NEJMra022219. [DOI] [PubMed] [Google Scholar]
  57. Shimizu I. Impact of oestrogens on the progression of liver disease. Liver Int. 2003;23:63–69. doi: 10.1034/j.1600-0676.2003.00811.x. [DOI] [PubMed] [Google Scholar]
  58. Smetana K, Jr., Rosel D, BrÁbek J. Raloxifene and bazedoxifene could be promising candidates for preventing the COVID-19 related cytokine storm, ARDS and mortality. In Vivo. 2020;34:3027–3028. doi: 10.21873/invivo.12135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Straub RH. The complex role of estrogens in inflammation. Endocr. Rev. 2007;28:521–574. doi: 10.1210/er.2007-0001. [DOI] [PubMed] [Google Scholar]
  60. Takeda M, Ikeda M, Mori K, Yano M, Ariumi Y, Dansako H, Wakita T, Kato N. Raloxifene inhibits hepatitis C virus infection and replication. FEBS Open Bio. 2012;2:279–283. doi: 10.1016/j.fob.2012.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Turner CH, Sato M, Bryant HU. Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology. 1994;135:2001–2005. doi: 10.1210/endo.135.5.7956922. [DOI] [PubMed] [Google Scholar]
  62. Tzukerman MT, Esty A, Santiso-Mere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP. Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol. Endocrinol. 1994;8:21–30. doi: 10.1210/mend.8.1.8152428. [DOI] [PubMed] [Google Scholar]
  63. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER, Jr., Wade JL, 3rd, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) p-2 trial. JAMA. 2006;295:2727–2741. doi: 10.1001/jama.295.23.joc60074. [DOI] [PubMed] [Google Scholar]
  64. WHO, World Health Organization. 2020. COVID-19 weekly epidemiological update, 17 November 2020. https://www.who.int/publications/m/item/weekly-epidemiological-update—-17-november-2020.
  65. Yang NN, Venugopalan M, Hardikar S, Glasebrook A. Identification of an estrogen response element activated by metabolites of 17β-estradiol and raloxifene. Science. 1996;273:1222–1225. doi: 10.1126/science.273.5279.1222. [DOI] [PubMed] [Google Scholar]
  66. Yoon YS, Jang Y, Hoenen T, Shin H, Lee Y, Kim M. Antiviral activity of sertindole, raloxifene and ibutamoren against transcription and replication-competent Ebola virus-like particles. BMB Rep. 2020;53:166–171. doi: 10.5483/BMBRep.2020.53.3.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zhang Y, Geng X, Tan Y, Li Q, Xu C, Xu J, Hao L, Zeng Z, Luo X, Liu F, et al. New understanding of the damage of SARS-CoV-2 infection outside the respiratory system. Biomed. Pharmacother. 2020;127:110195. doi: 10.1016/j.biopha.2020.110195. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Microbiology (Seoul, Korea) are provided here courtesy of Nature Publishing Group

RESOURCES