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LETTER TO EDITOR
Ahead of print publication  

Immunological prospects of tamoxifen as modern antiviral therapy


1 Department of Microbiology, Al-Shomali General Hospital, Babil, Iraq
2 Department of Immunology, Alsader Hospital, Najaf City, Iraq
3 Department of Medical Laboratories, Ahlulbait University, Kerbala, Iraq

Date of Submission06-Jun-2020
Date of Decision29-Jun-2020
Date of Acceptance30-Jun-2020
Date of Web Publication17-Sep-2020

Correspondence Address:
Falah AL-Khikani,
Department of Microbiology, Al-Shomali General Hospital, Babil
Iraq
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_72_20



How to cite this URL:
AL-Khikani F, Hameed R, Almosawey H. Immunological prospects of tamoxifen as modern antiviral therapy. J Mar Med Soc [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=295224



Sir,

Tamoxifen (TAM) is a nonsteroidal SERM of the triphenylethylene family and was structurally derived from diethylstilbestrol-like estrogens and anti-estrogens.[1] It was primarily discovered in 1962, by the scientist in chemistry, Dora Richardson.[2] Besides the effectiveness of TAM on malignant cells as breast cancer, it has other effects on numerous microbes including parasite and fungi. Recently, some studies focused on the potential antimicrobial action of TAM against some enveloped and nonenveloped viruses such as Ebola virus[3] and human immunodeficiency virus (HIV).[4] Furthermore, a recent study suggested using TAM to treat COVID-19 viral infection due to its unique properties as well as its immunomodulatory effect on immune responses by different mechanisms that may help the body to fight viral diseases.[5] Also, other drugs such as AmB[6] and ITZ.[7] have immunomodulatory effect suggested as antiviral drugs.

Viruses are considered the most numerous type of biological entity, and are found in almost every ecosystem on the earth.[8] There are difficult to treat viral infections, and some viruses have no specific therapy such as COVID 19.[9],[10],[11] Nearly 5000 species of viruses have been identified in detail, of the millions of virus types in the world.[8]

TAM, an anti-estrogen that competes for the estrogen receptor, modulates natural killer (NK) cell activity in vivo. It has been demonstrated that TAM can enhance murine NK activityin vivo and can enhance human NK activity in vitro.[12] Another study demonstrated that cytotoxic T lymphocyte-mediated, NK cell-mediated, and lymphokine-activated killer cell-mediated target cell lyses were amplified by TAM.[13] Most common drugs have adverse effect.[14],[15],[16],[17],[18] Also, some side effects associated with TAM.

NK cells are a type of innate immune cell, which responds immediately to new pathogens. It is the host's first line of defense against tumors and viral infection. NK cells kill cancerous or virally infected cells by recognizing certain molecules. In human lungs, NK cells are located in the parenchyma and are not detected outside the parenchyma, accounting for about 10%–20% of the lymphocytes.[19]

Numerous studies have described the effects of female sex hormones (steroid hormones estrogen) on NK cell activity. It is well established that sustained estrogen (β-estradiol) treatment of mice leads to a reduction inin vivo NK cell activity.[20] However, as TAM does not reduce estrogen levels in postmenopausal patients,[21] the enhancement of NK by TAM could not be ascribed to the reduction in serum estrogens.

A variety of DNA and RNA viruses have been shown to stimulate prostaglandin E2 (PGE2) production through cyclooxygenase (COX)-2 expression,[22] resulting in negative feedback in the regulation of macrophages and NK cells through inhibitory effects on interleukin-12 (IL-12) production and the expression of IL-12 receptors,[23] inhibiting interferon (IFN)-γ.[24] In NK cells, PGE2 functions by suppressing the responsiveness of IL-12 and IL-15, which suppresses the cytolytic effects of NK cells.[25] PGE2 abrogates the NK cell“helper” function by inhibiting the ability of NK cells to produce IFN-γ. Indeed, this documented ability of TAM to reduce PGE production may be the mechanism that resulted in the positive modulation of NK activity in both thein vivo andin vitro settings.[26]

Furthermore, PGE2 can play a role in viral infection directly by increasing the production and release of virions and stimulating viral gene expression. Because TAM decreased the PGE2 production,[27] targeted PGE2 may reduce viral replication and enhance antiviral immunity [Figure 1].
Figure 1: The effect of tamoxifen on immune response

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The activity of TAM toward herpes simplex virus type 1 (HSV-1) has been evaluated by one study which revealed that pretreatment or treatment with TAM and 5-nitro-2-(3-phenylpropylamino) benzoic acid at various time points during HSV-1 infection, suppressed viral RNA synthesis as well as expression of protein and virus production. A chloride channel inhibitory activity of TAM is thought to block HSV 1 fusion preventing viral binding, penetration, and nuclear translocation.[28]

Further studies have shown that TAM and other SERMs (raloxifene (RLX), the CLMs stereoisomers enclomiphene and zuclomiphene are also active against Ebola Virus, emerging treatment options for Ebola Virus Disease different strategies have been followed to target the virus and blocking viral entry.[29]

Thein vitro antiviral activity of TAM on the replication of HIV, hepatitis C virus, and HSV-1 had been evaluated. The effect of TAM on viral infection caused by vesicular stomatitis virus is by suppression viral RNA replication.[30]

One study which reviewed different therapeutic groups such as ER antagonists, kinase signaling inhibitors, protein-processing inhibitors, inhibitors of lipid or sterol metabolism and inhibitors of DNA synthesis or pair, and neurotransmitter inhibitors, suggested that TAM citrate and toremifene citratein vitro have antiviral effects on MERS-CoV at 10.11 μM and 12.91 μM, respectively, and 92.88 μM and 11.96 μM on SARS-CoV, respectively.[31] Some drugs have potential immunomodulatory properties that may enhance antiviral effects.[32],[33],[34],[35]

In conclusion, TAM can be used as antiviral therapy against some viral infections due to its ability to positive modulation of NK cells activity in both the in vivo and in vitro settings, reducing viral replication by decreasing PGE2 production as well as the unique properties of TAM to treat a viral infection.

As known, in viral infection immune system plays a crucial role in viral elimination, so using an antibiotic that has the ability to enhance immune response, activating innate immunity, and stimulate pro inflmmatory responses; like TAM may be very important to protect from some viral invasion. This effect has been associated with protective effects. TAM acts during infection, not only on the pathogen but also on the host. This issue is of particular interest because patients affected by viral infections may be immunocompromised. Consequently, TAM can be used as a potential antiviral drug particularly in immunocompromised patients by acting as an antiviral drug and enhancing immune responses by activating the positive immune modulation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Laurence J, Cooke H, Sikder SK. Effect of Tamoxifen on Regulation of Viral Replication and Human Immunodeficiency Virus (HIV) Long Terminal Repeat-Directed Transcription in Cells Chronically Infected with HIV-1; 1990. p. 696-703.  Back to cited text no. 4
    
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Almosawey HA, AL-Khikani FH, Hameed RM, Abdullah YJ, Al-Ibraheemi MK, Al-Asadi AA. Tamoxifen from chemotherapy to antiviral drug: Possible activity against COVID19. Biomed Biotechnol Res J 2020;4:1-9.  Back to cited text no. 5
    
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AL-Khikani FH. Amphotericin B as antiviral drug: Possible efficacy against COVID-19. Ann Thorac Med 2020;12:1-6.  Back to cited text no. 6
    
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Al-Khikani FH, Hameed RM. COVID-19 treatment: Possible role of itraconazole as new therapeutic option. Int J Health Allied Sci 2020;9:74-7.  Back to cited text no. 7
    
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Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China. Microbes Infect 2020;22:74-9.  Back to cited text no. 8
    
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AL-Khikani FH. Surveillance 2019 novel coronavirus (COVID-19) spreading: Is a terrifying pandemic outbreak is soon? Biomed Biotechnol Res J 2020;4:81-2.  Back to cited text no. 9
    
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AL-Khikani FH. The role of blood group in COVID-19 infection: More information is needed. J Nat Sci Med 2020;3:17-20.  Back to cited text no. 10
    
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AL-Khikani FH. COVID-19 and blood type: People with which group are more vulnerable? J Med Sci Res 2020;3:68-70.  Back to cited text no. 11
    
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Galino A, Santoni A, Screpanti I, Frat L. Antitumor antiestrogen stimulates natural killer (NK) activity in C3H mouse. J Leucocyte Biol 1985;38:159.  Back to cited text no. 12
    
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Baral E, Nagy E, Krepart GV, Lotocki RJ, Unruh HW, Berczi I. Antiestrogens sensitize human ovarian and lung carcinomas for lysis by autologous killer cells. Anticancer Res 2000;20:2027-31.  Back to cited text no. 13
    
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AL-Khikani FH. Pulmonary mycoses treated by topical amphotericin B. Biomed Biotechnol Res J 2020;4:24-8.  Back to cited text no. 14
    
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AL-Khikani FH. Refractory fungal vaginitis treated by topical amphotericin B. J Med Sci Res 2020;3:13-16.  Back to cited text no. 15
    
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AL-Khikani FH, Abadi RM, Ayit AS. Emerging carbapenemase Klebsiella oxytoca with multidrug resistance implicated in urinary tract infection. Biomed Biotechnol Res J 2020;4:66-8.  Back to cited text no. 16
    
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AL-Khikani FH, The forgotten role of methenamine to prevent recurrent urinary tract infection: urgency for reuse 100 years after discovery. Pharmaceutical Biomed Res 2020;6:13-16.  Back to cited text no. 17
    
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AL Khikani FH, Kadim BJ, Ayit AS, Abidalali MH. Evaluation cephalosporins resistance in pathogenic bacteria isolated clinically. World News of Natural Sciences 2020;31:110-9.  Back to cited text no. 18
    
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Hamerman JA, Ogasawara K, Lanier LL. NK cells in innate immunity. Curr Opin Immunol 2015;17:29-35.  Back to cited text no. 19
    
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Benten WP, Lieberherr M, Giese G, Wrehlke C, Stamm O, Sekeris CE, et al. Functional testosterone receptors in plasma membranes of T cells. FASEB J 1999;13:123-33.  Back to cited text no. 21
    
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Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 1997;159:28-35.  Back to cited text no. 23
    
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Snijdewint FG, Kaliński P, Wierenga EA, Bos JD, Kapsenberg ML. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol 1993;150:5321-9.  Back to cited text no. 24
    
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Bankhurst AD. The modulation of human natural killer cell activity by prostaglandins. J Clin Lab Immunol 1982;7:85-91.  Back to cited text no. 25
    
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Berry J, Green BJ, Matheson DS. Modulation of natural killer cell activity by tamoxifen in stage I post-menopausal breast cancer. Eur J Cancer Clin Oncol 1987;23:517-20.  Back to cited text no. 26
    
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Zheng K, Chen M, Xiang Y, Ma K, Jin F, Wang X, et al. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB. Biochem Biophys Res Commun 2014;446:990-6.  Back to cited text no. 28
    
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Bishop BM. Potential and emerging treatment options for Ebola virus disease. Ann Pharmacother 2015;49:196-206.  Back to cited text no. 29
    
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Cham LB, Friedrich SK, Adomati T, Bhat H, Schiller M, Bergerhausen M, et al. Tamoxifen protects from vesicular stomatitis virus infection. Pharmaceuticals 2019;12:142.  Back to cited text no. 30
    
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Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discovery Today 2020;19:45-9.  Back to cited text no. 31
    
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AL-Khikani FH. Amphotericin B from antifungal to antiviral therapy: promising modern therapeutic branch. Research Results in Pharmacology. 2020;6:57.  Back to cited text no. 32
    
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AL-Khikani FH, Ayit AS. Prospects in Immunomodulatory activity of Amphotericin B in viral infection: Promising developing therapeutic branch. Journal of Current Research in Scientific Medicine. 2020 ;6:65.  Back to cited text no. 33
    
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AL-Khikani FHO. Trends in Antibiotic Resistance of Major Uropathogens. Preprints 2020, 2020070104 (doi:10.20944/preprints202007.0104.v1).  Back to cited text no. 34
    
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AL Khikani FH. Immunomodulatory effect of amphotericin B enhances antiviral activity. Indian Journal of Medical Specialities. 2020;11:111.  Back to cited text no. 35
    


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