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Review
. 2022 Mar 30:13:879020.
doi: 10.3389/fphar.2022.879020. eCollection 2022.

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

Chiara Sfogliarini  1 , Giovanna Pepe  1 , Arianna Dolce  1 , Sara Della Torre  1 , Maria Candida Cesta  2 , Marcello Allegretti  2 , Massimo Locati  3   4 , Elisabetta Vegeto  1
Affiliations
Review

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

Chiara Sfogliarini et al. Front Pharmacol. .

Abstract

Beyond the wide use of tamoxifen in breast cancer chemotherapy due to its estrogen receptor antagonist activity, this drug is being assayed in repurposing strategies against a number of microbial infections. We conducted a literature search on the evidence related with tamoxifen activity in macrophages, since these immune cells participate as a first line-defense against pathogen invasion. Consistent data indicate the existence of estrogen receptor-independent targets of tamoxifen in macrophages that include lipid mediators and signaling pathways, such as NRF2 and caspase-1, which allow these cells to undergo phenotypic adaptation and potentiate the inflammatory response, without the induction of cell death. Thus, these lines of evidence suggest that the widespread antimicrobial activity of this drug can be ascribed, at least in part, to the potentiation of the host innate immunity. This widens our understanding of the pharmacological activity of tamoxifen with relevant therapeutic implications for infections and other clinical indications that may benefit from the immunomodulatory effects of this drug.

Keywords: SERMs; drug repurposing; infections; macrophages; tamoxifen.

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Conflict of interest statement

MCC and MA were employed by Dompé Farmaceutici S.p.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Tamoxifen therapeutic regimen according to on- or off-target indications. Tamoxifen is administered at different concentrations and timings according to on-target, ERα-dependent or off-target, ERα-unrelated indications and may reach micromolar drug concentrations in patient plasma or tissues.
FIGURE 2
FIGURE 2
Tamoxifen off-target effects in macrophages. Tamoxifen regulates macrophage activation by inducing PI3K-NRF2 pathway, caspase-1 formation and by modulating lipid metabolism and calcium homeostasis, as well as other possible targets identified in other cell types, such as PKC and oxidative stress. These molecular mediators and cell responses may represent a host-mediated mechanism that contributes to the beneficial activity of tamoxifen against pathogen and viral infections.
See this image and copyright information in PMC

References

    1. Allegretti M., Cesta M. C., Zippoli M., Beccari A., Talarico C., Mantelli F., et al. (2022). Repurposing the Estrogen Receptor Modulator Raloxifene to Treat SARS-CoV-2 Infection. Cell Death Differ 29 (1), 156–166. 10.1038/s41418-021-00844-6 - DOI - PMC - PubMed
    1. Barreto G. E., Santos-Galindo M., Garcia-Segura L. M. (2014). Selective Estrogen Receptor Modulators Regulate Reactive Microglia after Penetrating Brain Injury. Front. Aging Neurosci. 6, 132. 10.3389/fnagi.2014.00132 - DOI - PMC - PubMed
    1. Bekele R. T., Venkatraman G., Liu R. Z., Tang X., Mi S., Benesch M. G., et al. (2016). Oxidative Stress Contributes to the Tamoxifen-Induced Killing of Breast Cancer Cells: Implications for Tamoxifen Therapy and Resistance. Sci. Rep. 6, 21164. 10.1038/srep21164 - DOI - PMC - PubMed
    1. Bewley M. A., Budd R. C., Ryan E., Cole J., Collini P., Marshall J., et al. (2018). Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists. Am. J. Respir. Crit. Care Med. 198 (6), 739–750. 10.1164/rccm.201705-0903OC - DOI - PMC - PubMed
    1. Bowie M. L., Dietze E. C., Delrow J., Bean G. R., Troch M. M., Marjoram R. J., et al. (2004). Interferon-Regulatory Factor-1 Is Critical for Tamoxifen-Mediated Apoptosis in Human Mammary Epithelial Cells. Oncogene 23 (54), 8743–8755. 10.1038/sj.onc.1208120 - DOI - PubMed

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