Tamoxifen is a compound used in breast cancer research and estrogen-related gynecomastia. It is a selective estrogen receptor modulator (SERM) and reduces growth of breast cancer cells, aling with its metabolite 4-hydroxytamoxifen. This member of the triphenylethylene group was initially manufactured in 1962 by chemist Dora Richardson (ICI, now part of AstraZeneca) and called Compound ICI 46,474. It was part of a project to design a new contraceptive pill but it was found to stimulate rather than suppress ovulation and was re-purposed to become the first preventative for any cancer. Without the efforts of the team lead and reproductive endocrinologist Artur Walpole, it may have not been pursued further. It was not until 1998 that the meta-analysis of the Early Breast Cancer Trial Collabrative Group showed that it was effective for early breast cancer. Structurally, it is closely related to other triphenylethylenes like clomifene, nafoxidine, ospemifine, toremifene, and others.
| Mechanism of Action |
Tamoxifen is a prodrug and its metabolites bind to estrogen receptors in tumor cells which decrease DNA synthesis and inhibit estrogen effects. It has little affinity for the estrogen receptor itself and acts as a prodrug of active metabolites like endoxifen anad afimoxifene, which have 30-100X greater affinity for the estrogen receptors than Tamoxifen. It is a protein kinase C inhibitor leading to apoptosis in malignant glioma cell lines. It activates heat shock protein 90 (Hsp90) and enhances the Hsp90 molecular chaperone ATPase activity. |
| Cancer Applications |
Tamoxifen is a selective estrogen receptor modulator and reduces growth of breast cancer cells. It binds to estrogen receptor competitively in tumor cells, resulting in a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It causes cells to stay in the Go and G1 phases. Since it prevents pre- cancerous cells from dividing but does not cause cell death, it is considered cytostatic rather than cytocidal. Despite being an estrogen receptor (ER) antagonist in breast tissue so that estrogen-responsive genes are inhibited, it acts as a partial agonist on the endometrium and has been linked to endometrial cancer. It has predominantly antiestrogenic effects in breast tissue, but estrogenic effects in other cells such as bone, liver, and uterine cells. Tamoxifen and its active metabolite 4-hydroxytamoxifen were identified as a putative Hsp90 ligand during a virtual screening approach. Surprisingly, they enhanced Hsp90 ATPase. Hep90 is an essential molecular chaperone but also a novel anti-cancer target. |
| Molecular Formula | C26H29NO |
| References |
Clemons MS, Danson and Howell A (2002) Tamoxifen (‘Nolvadex’): A Review." Cancer Treatment Reviews 28 (4):165-80 Day CM, Hickey SM, Song Y, Plush SE, Garg S (2020) Novel Tamoxifen nanoformulations for improving breast cancer treatment: Old wine in new bottles. Molecules. 25(5):1182 PMID 32151063 Quirke VM (2017) Tamoxifen from failed contraceptive pill to best-selling breast cancer medicine: A case-study in pharmaceutical innovation. Front Pharmacol. 8:620 PMID 28955226 Zhao R, Leung E, Grüner S, Schapira M, Houry WA (2010) Tamoxifen enhances the Hsp90 molecular chaperone ATPase activity. PLoS One. 5(4):e9934 PMID 20376192 |