Sandrine Poirot

French Institute of Health and Medical Research | Inserm · Cholesterol metabolism and therapeutic innovations

Oncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha positive breast cancer (ER(+) BC) and triple negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α- or β- isomers of 5,6-epoxycholestanols (5,6-E...

Oncosterone (6-oxo-cholestane-3β,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha positive breast cancer (ER(+) BC) and triple negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α-or β-isomers of 5,6-epoxycholestanols (5,6-EC)...

Cholesterol-5,6-epoxides (5,6-ECs) are oxysterols (OS) that have been linked to several pathologies including cancers and neurodegenerative diseases. 5,6-EC can be produced from cholesterol by several mechanisms including reactive oxygen species, lipoperoxidation, and cytochrome P450 enzymes. 5,6-EC exists as two different diastereoisomers: 5,6α-EC...

Cholestane-3β,5α,6β-triol (CT) is a primary metabolite of 5,6-epoxycholesterols (5,6-EC) that is catalyzed by the cholesterol-5,6-epoxide hydrolase (ChEH). CT is a well-known biomarker for Niemann-Pick disease type C (NP-C), a progressive inherited neurodegenerative disease. On the other hand, CT is known to be metabolized by the 11β-hydroxysteroid...

Cholesterol plays important roles in many physiological processes, including cell membrane structure and function, hormone synthesis, and the regulation of cellular homeostasis. The role of cholesterol in breast cancer is complex, and some studies have suggested that elevated cholesterol levels may be associated with an increased risk of developing...

Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamo...

Normal cells secrete small extracellular vesicles (sEV), containing exosomes and/or ectosomes, which play a beneficial role in monitoring tissue integrity and immune response, whereas cancer cells constitutively secrete sEV, which contribute to inhibit the immune defenses and promote tumor progression and aggressiveness. Therefore, there is a great...

Vitamin E components and vitamin E oxidation products (VEOP) define the “vitaminEome”. VEOP are produced through biological and chemical processes. They are found at low concentrations in vivo and may play particular biological functions linked with chemoprevention and inflammatory processes. Much data have been reported leading to more insight int...

Tumour cells are characterized by having lost their differentiation state. They con-stitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which...

Delaying and even reversing ageing is a major public health challenge with a tremendous potential to postpone a plethora of diseases including cancer, metabolic syndromes and neurodegenerative disorders. A better understanding of ageing as well as the development of innovative anti-ageing strategies are therefore an increasingly important field of...

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likel...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

the PDF can be download freely on pubmed. https://pubmed.ncbi.nlm.nih.gov/33634751/

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

Simple Summary Recently, several molecules have improved the clinical outcome of acute myeloid leukemia (AML) patients. Despite these recent advances, their prognosis remains poor and new strategies to improve the standard anthracycline and Ara-C-based chemotherapy are needed. We recently published that dendrogenin A (DDA), a mammalian cholesterol...

Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. This is illustrated by the recent discovery of a cholesterol metabolic branch involving the biochemical transformation of 5,6-epoxycholesterols (5,6-ECs). 5,6-ECs have been shown to be differentially metabolized i...

Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. Recently, a new branch of cholesterol metabolism has been discovered involving the biochemical transformation of 5,6‐epoxycholesterols (5,6‐ECs). The 5,6‐ECs are metabolized in breast cancers to the tumour promote...

Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticance...

Dendrogenin A (DDA) is a newly-discovered steroidal alkaloid, which remains to date the first ever found in mammals. DDA is a cholesterol metabolites that induces cancer cell differentiation and death in vitro and in vivo, and thus behave like a tumor suppressor metabolite. Preliminary studies performed on 10 patients with estrogen receptor positiv...

Dendrogenin A (DDA) is a tumor suppressor mammalian cholesterol-derived metabolite and a new class of ligand of the Liver X receptor (LXR), which displays tumor cell differentiation. In human MCF7 breast adenocarcinoma cells, DDA-induced cell differentiation was associated with an increased accumulation of neutral lipids and proteins found in milk...

Liver X receptors (LXRs) α (NR1H3) and β (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies...

Vitamin E refers to functional food and dietary nutrients that play an important role for maintaining human health and its nutritional status. Vitamin E is mainly known as an antioxidant, which struggles free radicals and protects cells against damages and human body against aging. Vitamin E components were proposed to prevent against some chronica...

It has been very recently shown how naturally occurring oxyprenylated coumarins are effective modulators of melanogenesis. In this short communication we wish to generalize the potentialities as skin tanning or whitening agents of a wider panel of natural and semisynthetic aromatic compounds, including coumarins, cinnamic and benzoic acids, cinnama...

This abstract was not presented at the conference. Citation Format: Mallinger A, Dalenc F, Poirot M, Silvente-Poirot S. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-10.

Umbelliprenin has recently been shown to have great potential as a skin whitening agent. Wishing to investigate the same effect in plant species known to biosynthesize this coumarin, three plants belonging to the Apiaceae family, namely Anethum graveolens L. (dill), Pimpinella anisum L. (anise), and Ferulago campestris (Besser) Grecescu (field feru...

Dendrogenin A (DDA) is a tumor suppressor metabolite identified in human tissues that arises from the conjugation of 5,6α-epoxycholesterol (5,6α-EC) with histamine (HA) by a yet unidentified enzyme. DDA is present in the normal breast but its levels were found drastically decreased in breast tumors, showing that a deregulation of DDA metabolism occ...

Epidemiological studies are controversial concerning the roles played by cholesterol in cancer risk and development, possibly as it is not cholesterol per se that is pathological in cancers. Indeed, recent data reveal that the cholesterol metabolism in cancer cells can generate endogenous oncopromoter metabolites at higher levels compared to normal...

Intercellular communication has been known for decades to involve either direct contact between cells or to operate by spreading molecules such as cytokines, growth factors, or lipid mediators. Through the last decade we have begun to appreciate the increasing importance of intercellular communication mediated by extracellular vesicles released by...

Oxygenation products of cholesterol, named oxysterols, were suspected since the 20th century to be involved in carcinogenesis. Among the family of oxysterol molecules, cholesterol-5,6-epoxides (5,6-EC) retained the attention of scientists because they contain a putative alkylating epoxide group. However, studies failed into demonstrating that 5,6-E...

Bryonolic acid (BrA) is a pentacyclic triterpene present in several plants used in African 15 traditional medicine such as Anisophyllea dichostyla R. Br.. Here we investigated the in vitro 16 anticancer properties of BrA. We report that BrA inhibits acyl-coA: cholesterol acyl transferase 17 (ACAT) activity in rat liver microsomes in a concentration...

Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies sh...

Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autoph...

Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressorproperties. Here, we explored its efficacy and mechanism of cell death in melanoma andacute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro andin vivo, including primary AML patient samples, independently of melanoma Braf status orAML m...

Synthesis and cellular evaluation of new bi-specific estrogen receptor modulators and ACAT inhibitors as anticancer agents

Significance Cholesterol and its transformation into cholesterol-5,6-epoxides (5,6-EC) was long suspected as contributing to breast cancer (BC) pathogenesis, before it was found that 5,6-EC metabolism controls BC development and is deregulated in breast cancers. Herein, we studied in tumor cells and human samples how 5,6-EC metabolism deregulation...

Dendrogenin A (DDA) was recently identified as a mammalian cholesterol metabolite that displays tumor suppressor and neurostimulating properties at low doses. In breast tumors, DDA levels were found to be decreased compared to normal tissues, evidencing a metabolic deregulation of DDA production in cancers. DDA is an amino-oxysterol that contains t...

Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquir...

5,6α-epoxycholesterol (5,6α-EC) and 5,6β-epoxycholesterol (5,6β-EC) are oxysterols involved in the anticancer pharmacology of the widely used antitumor drug tamoxifen. They are both metabolized into cholestane-3β,5α,6β-triol (CT) by the cholesterol-5,6-epoxide hydrolase (ChEH) enzyme, and CT is metabolized by an as-yet uncharacterized enzyme into 6...

Introduction Mammographic density (MD), created predominantly by increased stromal tissue, is a major risk factor for breast cancer, though little is known about the biological mechanisms mediating it. Tamoxifen prevents breast cancer in a subset of high-risk women via mechanisms that appear dependent on reduction of MD. Animal models suggest tamox...

Accumulating evidence indicates that cholesterol oxygenation products, also known as oxysterols (OS), are involved in breast cancer (BC) promotion. The impact of Tam, as well as aromatase inhibitors (AI), an alternative BC endocrine therapy (ET), on OS metabolism in patients is currently unknown. We conducted a prospective clinical study in BC pati...

Tamoxifen (Tam) was developed as a ligand and modulator of estrogen receptor α (ERα) and is one of the main drugs used globally for the hormonotherapy of breast cancers. Besides ERα, Tam also binds with high affinity to the microsomal antiestrogen binding site (AEBS). The AEBS is a hetero-oligomeric proteinaceous complex with cholesterol-5,6-epoxid...

Dendrogenin A (DDA) is the first steroidal alkaloid (SA) to be identified in human tissues to date and arises from the stereoselective enzymatic conjugation of 5,6α-epoxycholesterol (5,6α-EC) with histamine (HA). DDA induces the re-differentiation of cancer cells in vitro and in vivo and prevents breast cancer (BC) and melanoma development in mice,...

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring au...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

Tocols are vitamin E compounds that include tocopherols (TP) and tocotrienols (TT). These lipophilic compounds are phenolic antioxidants and are reportedly able to modulate estrogen receptor β (ERβ). We investigated the molecular determinants that control their estrogenicity and effects on the proliferation of breast cancer cells. Docking experimen...

Tocols are vitamin E compounds that include tocopherols (TPs) and tocotrienols (TTs). These lipophilic compounds are phenolic antioxidants and are reportedly able to modulate estrogen receptor β (ERβ). We investigated the molecular determinants that control their estrogenicity and effects on the proliferation of breast cancer cells. Docking experim...

To investigate the therapeutic potential for treating inner ear damage of two new steroidal alkaloid compounds, Dendrogenin A and Dendrogenin B, previously shown to be potent inductors of cell differentiation. Guinea pigs, unilaterally deafened by neomycin infusion, received a cochlear implant followed by immediate or a 2-week delayed treatment wit...

Breast cancer (BC) is the most common female cancer. Although hormonotherapy (HT), such as Tamoxifen (Tam), is effective for the treatment of most patients with BC expressing estrogen receptors (ER +), resistance to HT is frequent and a number of BC do not express these receptors and do not respond to HT. The mechanisms responsible for these treatm...

Cholesterol-5, 6-epoxide hydrolase (ChEH) in mammals is a hetero-oligomeric complex of two cholesterogenic enzymes that control mammalian developmental programs. Following the identification of this complex, it was hypothesized that a new metabolic pathway existed that centered on 5, 6-epoxy cholesterols (5,6-EC). Conjugation products of 5,6-EC wit...

Background: Clinicians need new predictive biomarkers of response to hormonal therapy in patients (pts) with hormone receptor-positive (HR+) breast cancer (BC). Current treatments used the selective estrogen receptor modulator tamoxifen (Tam) or aromatase inhibitors (AI). Several data from the literature and our preclinical results indicate that ch...

Sterol derivatives of formula (I) and a method for the production of the compounds, a medicament using one of the compounds and a pharmaceutical composition comprising the medicament.

Acute Myeloid Leukemia (AML) is the most common type of leukemia in adults. Despite intensive research, current treatments remain unsatisfactory with only 40% of younger (<60 years) and less than 10% of older (>60 years) AML patients achieving long-term complete remission. Consequently, drugs with novel mechanism of action are urgently needed to im...

Cholesterol metabolites can promote or suppress breast cancer, raising questions about how therapies might disrupt this balance.

Cholesterol Epoxide Hydrolase (ChEH) selectively catalyses the hydrolysis of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6β-epoxy-cholesterol (5,6β-EC) into cholestane-3β,5α,6β-triol (CT). We recently reported that the ChEH activity is carried out by the anti-estrogen binding site (AEBS), formed by 3β-hydroxysterol-Δ⁷-reductase (DHCR7) and 3β-hydroxyste...

Dysregulation of lipid metabolism involves cellular communication mediated by cell contacts or exchange of bioactive lipids bound to soluble carriers or to lipoproteins. An increasing field is that of cellular communication mediated by nanovesicles called exosomes. Those vesicles are released from an internal compartment of viable cells, circulate...

Multiple myeloma (MM) is a malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Despite extensive efforts to design drugs targeting tumoral cells and their microenvironment, MM remains an incurable disease for which new therapeutic strategies are needed. We demonstrated here that antiestrogens (AEs) belonging to s...

We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in can...

Supplementary Figures S1-S8 and Supplementary Tables S1-S3

Dendrogenin A (DDA) is a steroidal alkaloid that we recently discovered in mammalian tissues and normal cells. We did not detect DDA in a panel of melanoma and breast cancer cells, while DDA was present in normal Human Mammary Epithelial Cells and normal Human Epidermal Melanocytes suggesting that a deregulation of DDA metabolism may occur during c...

Tamoxifen (Tam) is a selective estrogen receptor modulator (SERM) that remains one of the major drugs used in the hormonotherapy of breast cancer (BC). In addition to its SERM activity, we recently showed that the oxidative metabolism of cholesterol plays a role in its anticancer pharmacology. We established that these effects were not regulated by...