From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite

Silvente-Poirot, Sandrine; Médina, Philippe de; Record, Michel; Poirot, Marc

doi:10.1016/j.biochi.2016.05.016

Cited by 22 publications

(15 citation statements)

References 51 publications

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“…To-date, no enzyme with cholesterol-5,6-epoxidase activity has been reported. However, the two isomers 5α,6α-EC and 5β,6β-EC can both be hydrolysed by cholesterol-5,6-epoxide hydrolase (ChEH) to cholestane-3β,5α,6β-triol (3β,5α,6β-triol) (Figure 3) (22**). 5,6-EC can also be hydrolysed under acidic condition to 3β,5α,6β-triol during sample handling procedures.…”

Section: β-Hydroxycholestan-56-epoxide and Cholestane-3β5α6β-triolmentioning

confidence: 99%

“…Interestingly, the enzyme is made up of two subunits, 3β-hydroxysteroid-Δ 8,7 -isomerase (D8D7I) and DHCR7, and is identical to the microsomal protein complex antiestrogen binding site (AEBS) which binds to tamoxifen, the anticancer drug, with high affinity. Inhibition of ChEH activity by tamoxifen binding induced cancer cell-differentiation through accumulation of 5,6-EC (22). These findings lead Poirot and colleagues to search for a metabolite of 5,6-EC, other than those generated from 3β,5α,6β-triol, that may be display anticancer properties.…”

Section: Dendrogenin Amentioning

confidence: 99%

“…These findings lead Poirot and colleagues to search for a metabolite of 5,6-EC, other than those generated from 3β,5α,6β-triol, that may be display anticancer properties. They discovered dendrogenin A (DDA), a 6β-histamine adduct of 5α,6α-EC (Figure 3) (22). DDA was found to display anticancer properties in vitro and in vivo .…”

Section: Dendrogenin Amentioning

confidence: 99%

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Unravelling new pathways of sterol metabolism

Wang

Griffiths

2018

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of reviewTo update researchers of recently discovered metabolites of cholesterol and of its precursors and to suggest relevant metabolic pathways.Recent findingsPatients suffering from inborn errors of sterol biosynthesis, transport and metabolism display unusual metabolic pathways, which may be major routes in the diseased state but minor in the healthy individual. Although quantitatively minor, these pathways may still be important in healthy individuals. Four inborn errors of metabolism, Smith-Lemli-Opitz syndrome, cerebrotendinous xanthomatosis and Niemann Pick disease types B (NPB) and C (NPC) result from mutations in different genes but can generate elevated levels of the same sterol metabolite, 7-oxocholesterol, in plasma. How this molecule is metabolized further is of great interest as its metabolites may have an important role in embryonic development. A second metabolite, abundant in NPC and NPB diseases, cholestane-3β,5α,6β-triol (3β,5α,6β-triol), has recently been shown to be metabolized to the corresponding bile acid, 3β,5α,6β-trihydroxycholanoic acid, providing a diagnostic marker in plasma. The origin of cholestane-3β,5α,6β-triol is likely to be 3β-hydroxycholestan-5,6-epoxide, which can alternatively be metabolized to the tumour suppressor dendrogenin A (DDA). In breast tumours, DDA levels are found to be decreased compared with normal tissues linking sterol metabolism to cancer.SummaryUnusual sterol metabolites and pathways may not only provide markers of disease, but also clues towards cause and treatment.

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Section: β-Hydroxycholestan-56-epoxide and Cholestane-3β5α6β-triolmentioning

confidence: 99%

Section: Dendrogenin Amentioning

confidence: 99%

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Unravelling new pathways of sterol metabolism

Wang

Griffiths

2018

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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“…Tamoxifen (TAM) is the oldest and most-prescribed selective estrogen receptor modulator, that has been approved to treat women and men diagnosed with hormonal receptor (HR + ), early-stage BC after surgery to reduce the risk of the cancer recurrence as well as treatment of advanced-stage or metastatic HR + BC patients [ 7 , 8 , 9 ]. The combination of high efficacy in both pre- and postmenopausal women and a good tolerability profile of TAM lead to maintain its position as drug of choice for most patients with HR + breast cancer [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen and the PI3K Inhibitor: LY294002 Synergistically Induce Apoptosis and Cell Cycle Arrest in Breast Cancer MCF-7 Cells

et al. 2020

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Breast cancer is considered as one of the most aggressive types of cancer. Acquired therapeutic resistance is the major cause of chemotherapy failure in breast cancer patients. To overcome this resistance and to improve the efficacy of treatment, drug combination is employed as a promising approach for this purpose. The synergistic cytotoxic, apoptosis inducing, and cell cycle effects of the combination of LY294002 (LY), a phosphatidylinositide-3-kinase (PI3K) inhibitor, with the traditional cytotoxic anti-estrogen drug tamoxifen (TAM) in breast cancer cells (MCF-7) were investigated. LY and TAM exhibited potent cytotoxic effect on MCF-7 cells with IC50 values 0.87 µM and 1.02 µM. The combination of non-toxic concentration of LY and TAM showed highly significant synergistic interaction as observed from isobologram (IC50: 0.17 µM, combination index: 0.18, colony formation: 9.01%) compared to untreated control. The percentage of early/late apoptosis significantly increased after treatment of MCF-7 cells with LY and TAM combination: 40.3%/28.3% (p < 0.001), compared to LY single treatment (19.8%/11.4%) and TAM single treatment (32.4%/5.9%). In addition, LY and TAM combination induced the apoptotic genes Caspase-3, Caspase-7, and p53, as well as p21 as cell cycle promotor, and significantly downregulated the anti-apoptotic genes Bcl-2 and survivin. The cell cycle assay revealed that the combination induced apoptosis by increasing the pre-G1: 28.3% compared to 1.6% of control. pAKT and Cyclin D1 protein expressions were significantly more downregulated by the combination treatment compared to the single drug treatment. The results suggested that the synergistic cytotoxic effect of LY and TAM is achieved by the induction of apoptosis and cell cycle arrest through cyclin D1, pAKT, caspases, and Bcl-2 signaling pathways.

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“…4) and Poirot and colleagues have shown that DDA causes cancer cell differentiation and has anticancer properties both in vitro and in vivo [53]. 5α,6-EC is usually thought of as a non-enzymatic product of cholesterol, but there is some evidence for its enzymatic formation [54], [55]. 5α,6-EC and its epimer, 5β,6-EC, are both ligands to the microsomal antiestrogen binding site (AEBS), a hetero-oligomeric protein to which tamoxifen, a drug which binds to the ERα receptor, also binds.…”

Section: Introductionmentioning

confidence: 99%

Cholesterolomics: An update

Griffiths

Abdel-Khalik

Yutuc

et al. 2017

Analytical Biochemistry

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Cholesterolomics can be regarded as the identification and quantification of cholesterol, its precursors post squalene, and metabolites of cholesterol and of its precursors, in a biological sample. These molecules include 1,25-dihydroxyvitamin D3, steroid hormones and bile acids and intermediates in their respective biosynthetic pathways. In this short article we will concentrate our attention on intermediates in bile acid biosynthesis pathways, in particular oxysterols and cholestenoic acids. These molecular classes are implicated in the aetiology of a diverse array of diseases including autoimmune disease, Parkinson's disease, motor neuron disease, breast cancer, the lysosomal storage disease Niemann-Pick type C and the autosomal recessive disorder Smith-Lemli-Opitz syndrome. Mass spectrometry (MS) is the dominant technology for sterol analysis including both gas-chromatography (GC)-MS and liquid chromatography (LC)-MS and more recently matrix-assisted laser desorption/ionisation (MALDI)-MS for tissue imaging studies. Here we will discuss exciting biological findings and recent analytical improvements.

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From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite

Cited by 22 publications

References 51 publications

Unravelling new pathways of sterol metabolism

Unravelling new pathways of sterol metabolism

Tamoxifen and the PI3K Inhibitor: LY294002 Synergistically Induce Apoptosis and Cell Cycle Arrest in Breast Cancer MCF-7 Cells

Cholesterolomics: An update

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