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tamoxifen (tamoxifen, Douglas)

✓ Approved

Douglas Pharmaceuticals Limited · ESR1 · Small Molecule

What is tamoxifen?

tamoxifen is a small molecule developed by Douglas Pharmaceuticals Limited. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand Namestamoxifen, Douglas
CompanyDouglas Pharmaceuticals Limited
Drug ClassSmall Molecule
Molecular TargetESR1
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, Douglas Pharmaceuticals Limited

Mechanism of Action

Molecular Targets

tamoxifen acts on 1 molecular target:

ESR1estrogen receptor 1 (ER, ESR)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

tamoxifen is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Breast cancer✓ Approved

Related Research Articles

PubMedCurrent molecular medicine2026-09-18

Tamoxifen and Colchicine Alter Mitochondrial Respiration to Induce Cell Death in Low-metastatic Breast Cancer Cells.

Singh Tashvinder T, Thankachan Amitha A, Munshi Anjana A, Singh Sandeep S

Breast cancer cells exhibit mitochondrial respiration-mediated metabolic heterogeneity and tumour aggressiveness. Tamoxifen and Colchicine are known to interfere with oxidative stress in breast cancer cells. However, their role in regulating mitochondrial respiration remains poorly understood. MCF7 and MDA-MB-231 cells were used to analyse the metabolic modulatory effects of Tamoxifen and Colchicine. The roles of Tamoxifen and Colchicine in regulating ROS production, mitochondrial membrane potential, mitochondrial membrane integrity, and oxidative phosphorylation were assessed using ROS assay, JC-1 assay, and high-resolution respirometry, respectively. Their effects on mitochondrial biogenesis and mitochondria-dependent cytotoxicity were analysed using flow cytometry and confocal microscopy. Tamoxifen and Colchicine exhibited cytotoxic effects by reducing ROS production, depolarising mitochondrial membrane potential, decreasing oxygen consumption, and inhibiting mitochondrial respiration. They specifically downregulated pyruvate-mediated mitochondrial respiration, preventing N-linked state mitochondrial respiration and reducing complex I activity. Colchicine demonstrated mitochondrialindependent cytotoxic effects, whereas Tamoxifen did not. Neither drug impacted mitochondrial membrane integrity. Tamoxifen and Colchicine decreased leak respiration, inhibited proton and electron transfer, and prevented non-phosphorylating electron transfer, potentially due to reduced complex I activity. Tamoxifen significantly inhibits mitochondrial biogenesis and induces a mitochondrial-dependent cell death pathway. In contrast, Colchicine had a low impact on mitochondrial biogenesis and induced a mitochondrial-independent cell death pathway. Tamoxifen and colchicine suppress complex I-driven mitochondrial respiration in breast cancer cells, reducing oxidative phosphorylation-associated aggressiveness. Notably, only tamoxifen links this metabolic inhibition to impaired mitochondrial biogenesis and mitochondria-dependent cytotoxicity. Tamoxifen and colchicine downregulate mitochondrial respiration and biogenesis, while only tamoxifen induces mitochondrial-dependent cytotoxicity.

PMID 42755301
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PubMedJCI insight2026-09-17

Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts.

Chen Yintong Y, Xu Weiwei W, Yu Jieli J, Deng Pei P et al.

TGF-β is a central driver of kidney fibrosis, a common pathological hallmark of chronic kidney disease (CKD). Initiation of TGF-β signaling requires not only its synthesis but also the conversion of latent TGF-β to its bioactive form. However, the mechanisms governing TGF-β activation in the kidney and their contribution to kidney fibrosis remain poorly understood. Glycoprotein A repetitions predominant (GARP) anchors latent TGF-β on the cell surface and facilitates its bioactive release. Here, we show that GARP-mediated TGF-β activation promotes kidney fibrosis. GARP was upregulated in both human and mouse CKD kidneys, predominantly in fibroblasts, and was induced by TNF in an NF-kB-dependent fashion. In multiple mouse models of kidney fibrosis, either global or fibroblast-specific deletion of GARP significantly reduced fibrosis. Mechanistically, GARP enables sustained production of active TGF-β, thereby amplifying fibroblast stimulation. Deletion of GARP in kidney fibroblasts lowered active TGF-β levels and attenuated fibroblast activation, whereas GARP overexpression enhanced TGF-β signaling. Notably, tamoxifen-induced deletion of GARP after fibrosis onset attenuated kidney fibrosis. Together, our findings identify GARP-mediated release of active TGF-β as a critical step in sustaining fibroblast activation during kidney fibrosis and highlight GARP as a promising therapeutic target for CKD.

PMID 42752459
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PubMedAmerican journal of physiology. Lung cellular and molecular physiology2026-09-16

Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection.

Brune Jourdan E JE, Chang Mary Y MY, Tang Fengying F, Lopez-Martinez Cecilia C et al.

Viral and bacterial lung infections place a significant burden on public health. Versican, an extracellular matrix (ECM) chondroitin sulfate proteoglycan, coordinates the innate immune response in multiple experimental models. Versican's potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling the host's immune response to lung infection. However, versican's contribution to lung inflammation, injury, and immune cell activity during influenza A virus (IAV) infection represents a critical knowledge gap. To address our central hypothesis that mesenchymal-derived versican is pro-inflammatory and enhances the innate immune response to IAV infection, we generated a tamoxifen-inducible mouse deficient in mesenchymal-derived versican (B6. Col1a2-CreERT+/-/Vcantm1.1Cwf, Col1a2/Vcan-/-). We report that mesenchymal-derived versican plays a critical role in neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in IAV infection. Intriguingly, mesenchymal-derived versican deficiency had the most substantial negative impact on neutrophil emigration into the lungs. We found that neutrophils were less adhesive to the ECM of Col1a2/Vcan-/- mouse lung fibroblasts (mLFs), which had a significant decrease in versican compared to wild-type mLFs. Additionally, Col1a2/Vcan-/- mLFs treated with poly(I:C) in vitro have reduced cell-associated hyaluronan. These findings suggest that fibroblast-derived versican is necessary for adhesion to lung fibroblasts by neutrophils as they transit into the lung interstitium and airways from the pulmonary vasculature. Our findings demonstrate that mesenchymal-derived versican is a key regulator of the early host immune responses to IAV.

PMID 42747347
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PubMedAmerican journal of physiology. Cell physiology2026-09-16

Endogenous calcium/calmodulin-dependent protein kinase II gamma and delta maintain Type II myofiber identity in adult mice.

Iwase Hikaru H, Ichihashi Yuka Y, Tsukahara Ryoka R, Kunieda Takuma T et al.

Skeletal muscle fiber identity is commonly characterized by coordinated contractile and metabolic programs, but the mechanisms that preserve this coordination in adult muscle remain unclear. We tested whether endogenous calcium/calmodulin-dependent protein kinase II γ and δ (CaMKIIγ/δ) maintain type II myofiber identity. Tamoxifen-inducible, skeletal muscle-specific Camk2g/Camk2d double-knockout mice were analyzed 1 and 3 mo after deletion using soleus fiber typing, laser microdissection proteomics, and immunofluorescence. CaMKIIγ/δ deletion was not associated with detectable changes in body weight or muscle mass but increased type I fibers and reduced total type II fibers at both time points, with a transient increase in type I/II hybrid fibers. Within mKO muscles, the type IIa fiber proportion declined over time. Fiber type-resolved proteomics revealed remodeling within fibers retaining a type II myosin heavy chain profile. Proteins enriched in control type I fibers shifted upward in knockout type II fibers, whereas type II-enriched proteins shifted downward. Consistently, a type I-like score derived from an independent single-myofiber proteomic dataset increased selectively in knockout type II fibers, supporting remodeling beyond myosin isoform switching. CaMKII abundance was higher in type II than in type I fibers. Unexpectedly, this type I-like remodeling was not accompanied by an oxidative shift: oxidative phosphorylation-related protein programs were reduced across type I, type II, and hybrid fibers. These findings identify endogenous CaMKIIγ/δ as a homeostatic regulator of adult type II myofiber identity and show that fiber identity-associated proteomic features and mitochondrial oxidative programs can be remodeled in divergent directions.

PMID 42747228
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PubMedToxicology letters2026-09-16

Functional perturbation reveals context-dependent contributions of nuclear receptors to drug-induced hepatic steatosis.

Guo Kaidi K, van den Beucken Twan T

Drug-induced hepatic steatosis is mediated by diverse molecular mechanisms, yet several nuclear receptors have been proposed as molecular initiating events or early key events within adverse outcome pathways for hepatic steatosis. However, direct functional evidence supporting these mechanistic roles in human-relevant experimental systems remains limited. The present study evaluated the contribution of selected nuclear receptors to drug-induced hepatic steatosis using complementary human hepatic in vitro models. Stable short hairpin RNA-mediated knockdown of individual nuclear receptors was established in HepG2 and differentiated HepaRG cells, followed by exposure to representative steatogenic drugs, including valproic acid, amiodarone, tamoxifen, and rifampicin. In parallel, primary human hepatocyte spheroids were used to compare drug-induced lipid accumulation with direct pharmacological activation of individual nuclear receptor pathways. While depletion of multiple nuclear receptors markedly affected oleic acid-induced lipid accumulation, drug-induced steatogenic responses exhibited predominantly selective and compound-specific receptor dependencies. In differentiated HepaRG cells, nuclear receptor depletion influenced basal lipid homeostasis more strongly than valproic acid-induced lipid accumulation. Conversely, direct activation of liver X receptor and peroxisome proliferator-activated receptors α and γ in primary human hepatocyte spheroids induced robust lipid accumulation, whereas most steatogenic drugs produced comparatively modest responses. These findings demonstrate that the contribution of individual nuclear receptors to drug-induced hepatic steatosis is highly compound- and context-dependent and cannot be explained by a single conserved receptor pathway. This study provides functional evidence from complementary human-relevant hepatic models that supports refinement of hepatic steatosis adverse outcome pathways and highlights the value of targeted perturbation strategies for mechanistic toxicology.

PMID 42749173
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PubMedCancer treatment reviews2026-09-16

Selective estrogen receptor degraders in premenopausal breast cancer: Biological activity and endpoint relevance in window of opportunity trials.

Dudău Ana-Maria AM, Zeghondy Jean J, Emile George G, Simon Camille C et al.

Selective estrogen receptor degraders (SERDs) have emerged as a key therapeutic class in hormone receptor-positive (HR+) breast cancer, combining estrogen receptor (ER) antagonism with direct receptor degradation. Despite this dual mechanism, pivotal trials of SERDs in premenopausal patients-across both metastatic and adjuvant settings-have mandated concurrent ovarian function suppression (OFS). Mechanistically, because ER undergoes continuous synthesis, both receptor antagonism and degradation require sustained occupancy of the ligand-binding domain. The central question is therefore one of competitive target engagement-whether oral SERDs can achieve and maintain adequate receptor occupancy in a high-estrogen premenopausal environment, independent of their intrinsic degradation efficiency. Reframing the debate around this competitive binding dynamic, rather than degradation capacity alone, offers a more mechanistically complete basis for evaluating OFS necessity in premenopausal patients. Window-of-opportunity (WOO) trials have offered an early opportunity to probe this question, consistently demonstrating rapid ER downregulation and antiproliferative activity with SERD monotherapy. Yet interpretation of these findings is complicated by substantial heterogeneity across trials in patient selection, comparator design, treatment duration, tissue sampling strategy, and endpoint definition. Moreover, the endpoints most used to gauge pharmacodynamic response-Ki67 suppression and complete cell cycle arrest (CCCA)-were validated in postmenopausal populations treated with aromatase inhibitors or tamoxifen, agents that act primarily through estrogen deprivation or competitive antagonism rather than receptor degradation. Their applicability to SERDs, and to the distinct estrogen milieu of premenopausal patients, remains under investigation. This narrative review critically summarizes the development of oral SERDs in metastatic HR+ breast cancer, review findings from window-of-opportunity trials, discuss emerging evidence in premenopausal women and addresses the methodological variability, underlying biological considerations, and limitations of conventional pharmacodynamic endpoints.

PMID 42748873
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