Dendrogenin A and B two new steroidal alkaloids increasing neural responsiveness in the deafened guinea pig

Aim: 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. Methods: Guinea pigs, unilaterally deafened by neomycin infusion, received a cochlear implant followed by immediate or a two-week delayed treatment with Dendrogenin A, Dendrogenin B, and, as comparison artificial perilymph and glial cell-line derived neurotrophic factor. After a 4-week treatment period the animals were sacrificed and the cochleae processed for morphological analysis. Electrically-evoked auditory brainstem responses were measured weekly throughout the experiment. Results: Following immediate or delayed Dendrogenin treatment the electrical responsiveness was significantly maintained, in a similar extent as has been shown using neurotrophic factors. Histological analysis showed that the spiral ganglion neurons density was only slightly higher than the untreated group. Conclusions: Our results suggest that Dendrogenins constitute a new class of drugs with strong potential to improve cochlear implant efficacy and to treat neuropathy/synaptopathy related hearing loss. That electrical responsiveness was maintained despite a significantly reduced neural population suggests that the efficacy of cochlear implants is more related to the functional state of the spiral ganglion neurons than merely their number

Oxysterols and related sterols: Implications in pharmacology and pathophysiology.

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Cholesterol metabolism and cancer: the good, the bad and the ugly.

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When cholesterol meets histamine, it gives rise to dendrogenin A: a tumour suppressor metabolite1

International audienceDendrogenin 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 cellsin vitroandin vivoand prevents breast cancer (BC) and melanoma development in mice, evidencing its protective role against oncogenesis. In addition, DDA production is lower in BCs compared with normal tissues, suggesting a deregulation of its biosynthesis during carcinogenesis. The discovery of DDA reveals the existence of a new metabolic pathway in mammals which lies at the crossroads of cholesterol and HA metabolism and which leads to the production of this metabolic tumour suppressor

The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers

International audienceDendrogenin 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 showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3β,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors. Importantly, by binding the liver X receptor (LXR), DDA activates the expression of genes controlling autophagy. These genes include NR4A1, NR4A3, LC3 and TFEB. The canonical LXR ligands 22(R)hydroxycholesterol, TO901317 and GW3965 did not induce these effects indicating that DDA delineates a new class of selective LXR modulator (SLiM). The induction of lethal autophagy by DDA was associated with the accumulation in cancer cells of lysosomes and of the pro-lysosomal cholesterol precursor zymostenol due to the inhibition of the 3β-hydroxysteroid-Δ8Δ7-isomerase enzyme (D8D7I). The anti-cancer efficacy of DDA was established on different mouse and human cancers such as breast cancers, melanoma and acute myeloid leukemia, including patient derived xenografts, and did not discriminate bulk cancer cells from cancer cell progenitors. Together these data highlight that the mammalian metabolite DDA is a promising anticancer compound with a broad range of anticancer applications. In addition, DDA and LXR are new actors in the transcriptional control of autophagy and DDA being a "first in line" driver of lethal autophagy in cancers via the LXR

Cholesterol-5,6-epoxides: Chemistry, biochemistry, metabolic fate and cancer.

International audienceIn the nineteen sixties it was proposed that cholesterol might be involved in the etiology of cancers and cholesterol oxidation products were suspected of being causative agents. Researchers had focused their attention on cholesterol-5,6-epoxides (5,6-ECs) based on several lines of evidence: 1) 5,6-ECs contained an oxirane group that was supposed to confer alkylating properties such as those observed for aliphatic and aromatic epoxides. 2) cholesterol-5,6-epoxide hydrolase (ChEH) was induced in pre-neoplastic lesions of skin from rats exposed to ultraviolet irradiations and ChEH was proposed to be involved in detoxification processes like other epoxide hydrolases. However, 5,6-ECs failed to induce carcinogenicity in rodents which ruled out a potent carcinogenic potential for 5,6-ECs. Meanwhile, clinical studies revealed an anomalous increase in the concentrations of 5,6β-EC in the nipple fluids of patients with pre-neoplastic breast lesions and in the blood of patients with endometrious cancers, suggesting that 5,6-ECs metabolism could be linked with cancer. Paradoxically, ChEH has been recently shown to be totally inhibited by therapeutic concentrations of tamoxifen (Tam), which is one of the main drugs used in the hormonotherapy and the chemoprevention of breast cancers. These data would suggest that the accumulation of 5,6-ECs could represent a risk factor, but we found that 5,6-ECs were involved in the induction of breast cancer cell differentiation and death induced by Tam suggesting a positive role of 5,6-ECs. These observations meant that the biochemistry and the metabolism of 5,6-ECs needed to be extensively studied. We will review the current knowledge and the future direction of 5,6-ECs chemistry, biochemistry, metabolism, and relationship with cancer

Cholesterol epoxide hydrolase and cancer.

International audienceCholesterol epoxide hydrolase (ChEH) catalyzes the hydration of cholesterol-5,6-epoxides (5,6-EC) into cholestane-3β,5α,6β-triol. ChEH is a hetero-oligomeric complex called the anti-estrogen binding site (AEBS) comprising 3β-hydroxysterol-Δ(8)-Δ(7)-isomerase (D8D7I) and 3β-hydroxysterol-Δ(7)-reductase (DHCR7). D8D7I and DHCR7 regulate cholesterol biosynthesis, fetal development and growth, tumor cell differentiation and death. The un-reactivity of 5,6-EC toward nucleophiles has recently been demonstrated indicating that 5,6-EC are not alkylating and carcinogenic agents as first postulated. Here we discuss recent advances in the molecular characterization of ChEH, its potential role in cancer progression and resistance as well as the interest of inhibiting ChEH and to accumulate 5,6-EC which may contribute to the anti-tumor and chemopreventive action of ChEH inhibitors used in the clinic such as tamoxifen

Oxysterols: An expanding family of structurally diversified bioactive steroids

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Cancer. Cholesterol and cancer, in the balance.

International audienceMammalian cells synthesize cholesterol through a series of 21 enzymatic steps, generating numerous metabolites that are involved in the control of physiological and developmental processes. Cholesterol itself is the precursor of steroid hormones and sterols, the latter of which can be further modified into molecules that induce specific biological responses. Epidemiological studies have investigated the role of cholesterol in breast cancer risk, with contradictory findings. Recent studies, however, linking cholesterol metabolism to breast cancer may provide some insights. Certain cholesterol metabolites can promote (1, 2) or suppress (3) breast cancer. This raises the important question of how to regulate or inhibit the cholesterol metabolic pathway, and at which steps, in a therapeutic approach to cancer