Pharmacological Relevance of Endoxifen in a Laboratory Simulation of Breast Cancer in Postmenopausal Patients

Maximov, Philipp Y.; McDaniel, Russell E.; Fernandes, Daphne J.; Bhatta, Puspanjali; Korostyshevskiy, Valeriy R.; Curpăn, Ramona; Jordan, V. Craig

doi:10.1093/jnci/dju283

Cited by 16 publications

(9 citation statements)

References 47 publications

(45 reference statements)

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“…1e). This is within 10-fold of published cellular EC 50 values for Endoxifen, which range between 1-10 nM [20][21][22] .…”

Section: Resultssupporting

confidence: 81%

Chaperone mediated detection of small molecule target binding in cells

Cho¹,

Taylur²,

Rose³

et al. 2020

Nat Commun

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The ability to quantitatively measure a small molecule's interactions with its protein target(s) is crucial for both mechanistic studies of signaling pathways and in drug discovery. However, current methods to achieve this have specific requirements that can limit their application or interpretation. Here we describe a complementary target-engagement method, HIPStA (Heat Shock Protein Inhibition Protein Stability Assay), a high-throughput method to assess small molecule binding to endogenous, unmodified target protein(s) in cells. The methodology relies on the change in protein turnover when chaperones, such as HSP90, are inhibited and the stabilization effect that drug-target binding has on this change. We use HIPStA to measure drug binding to three different classes of drug targets (receptor tyrosine kinases, nuclear hormone receptors, and cytoplasmic protein kinases), via quantitative fluorescence imaging. We further demonstrate its utility by pairing the method with quantitative mass spectrometry to identify previously unknown targets of a receptor tyrosine kinase inhibitor.

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“…1e). This is within 10-fold of published cellular EC 50 values for Endoxifen, which range between 1-10 nM [20][21][22] .…”

Section: Resultssupporting

confidence: 81%

Chaperone mediated detection of small molecule target binding in cells

Cho¹,

Taylur²,

Rose³

et al. 2020

Nat Commun

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“…The antiestrogenic activities of tamoxifen and metabolites can be different when investigated in different cell lines, or in the presence of estrogen concentrations [31, 32]. However, the in vitro experiments were conducted to obtain the relative antiestrogenic activities of tamoxifen and three metabolites.…”

Section: Discussionmentioning

confidence: 99%

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

Schultink

Alexi

Werkhoven

et al. 2016

Breast Cancer Res Treat

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Purpose Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL. Patients and methods The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices. Results An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47–0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48–0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients. Conclusions Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.

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“…13) to view these data based on the results previously discussed in the section describing the drift in cell populations in vitro if estrogen induced apoptosis is blocked by an inhibitor of cSrc. The principle of improving the antiestrogenic mixture of metabolites in both a premenopausal and postmenopausal patient environment has recently been modeled in vitro (194, 195). These studies represent the immediate effects of tamoxifen and metabolites of estrogen stimulated growth and gene regulation.…”

Section: Summary and Future Clinical Perspectivementioning

confidence: 99%

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

121

100

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The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

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Pharmacological Relevance of Endoxifen in a Laboratory Simulation of Breast Cancer in Postmenopausal Patients

Cited by 16 publications

References 47 publications

Chaperone mediated detection of small molecule target binding in cells

Chaperone mediated detection of small molecule target binding in cells

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

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