Importance of cholesterol and oxysterols metabolism in the pharmacology of tamoxifen and other AEBS ligands

Médina, Philippe de; Paillasse, Michaël R.; Ségala, Grégory; Khallouki, Farid; Brillouet, S.; Dalenc, Florence; Courbon, F.; Record, Michel; Poirot, Marc; Silvente-Poirot, Sandrine

doi:10.1016/j.chemphyslip.2011.05.005

Cited by 52 publications

(34 citation statements)

References 37 publications

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“…Furthermore both PrP and PrP Sc appear to be highly enriched in the recycling compartment , which contains high cholesterol levels (Wüstner et al, 2002;Hao et al, 2002). Interestingly, although both TAM and OHT are inhibitors of cholesterol biosynthesis (de Medina et al, 2011;de Medina et al, 2004;de Medina et al, 2009), TAM has also been shown to inhibit the exit of cholesterol from lysosomes resulting in a lipid storage disease phenotype, characterized by the accumulation of cholesterol-laden late endosomes/lysosomes (Suárez et al, 2004). We observed a similar effect of both TAM and OHT on cholesterol trafficking in our cellular models (Fig.…”

Section: Discussionsupporting

confidence: 70%

“…Furthermore, TAM and OHT have been shown to perturb cholesterol homeostasis and trafficking in different cancer cell types (Suárez et al, 2004;de Medina et al, 2004;de Medina et al, 2011). Importantly, TAM has been shown to inhibit the exit of cholesterol from lysosomes leading to the accumulation of cholesterol-laden late endosomes/lysosomes (Suárez et al, 2004).…”

Section: Oht and Tam Causes Redistribution Of Prpmentioning

confidence: 99%

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4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy

Marzo

Marijanovic

Browman

et al. 2013

Journal of Cell Science

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SummaryPrion diseases are fatal neurodegenerative disorders involving the abnormal folding of a native cellular protein, named PrP C , to a malconformed aggregation-prone state, enriched in beta sheet secondary structure, denoted PrP Sc . Recently, autophagy has garnered considerable attention as a cellular process with the potential to counteract neurodegenerative diseases of protein aggregation such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. Stimulation of autophagy by chemical compounds has also been shown to reduce PrP Sc in infected neuronal cells and prolong survival times in mouse models. Consistent with previous reports, we demonstrate that autophagic flux is increased in chronically infected cells. However, in contrast to recent findings we show that autophagy does not cause a reduction in scrapie burden. We report that in infected neuronal cells different compounds known to stimulate autophagy are ineffective in increasing autophagic flux and in reducing PrPSc . We further demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen lead to prion degradation in an autophagy-independent manner by diverting the trafficking of both PrP and cholesterol to lysosomes. Our data indicate that tamoxifen, a well-characterized, widely available pharmaceutical, may have applications in the therapy of prion diseases.

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Section: Discussionsupporting

confidence: 70%

Section: Oht and Tam Causes Redistribution Of Prpmentioning

confidence: 99%

4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy

Marzo

Marijanovic

Browman

et al. 2013

Journal of Cell Science

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“…Other data suggest that tamoxifen acts by blocking cholesterol biosynthesis, and that the sterol balance may determine whether autophagy acts in a protective vs. cytotoxic manner. 768,769 Finally, screens have identified small molecules that induce autophagy independently 510 Autophagy Volume 8 Issue 4…”

Section: 696mentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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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 autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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“…Ring strain, that is incurred from the sp 3 to sp 2 hybridization change (bond angle distortion), is higher than that of non-fused ring systems due to "conformational transmission" [14]. Perhaps this explains why the oxidative methods surveyed in Tables 1-5 occur exclusively through a radical mechanism.…”

Section: Introductionmentioning

confidence: 93%

“…Ring B oxidized sterols and steroids have shown anti-cancer activity [1][2][3]. 7-Ketodehydroepiandrosterone has been shown to improve the memory of mice [4] and 3-acetyl-7-oxo-DHEA increases the resting metabolism of persons on calorie restrictive diets [5].…”

Section: Introductionmentioning

confidence: 99%

A Short Review of Methods for the Allylic Oxidation of Δ5 Steroidal Compounds to Enones

Sg¹,

Jp²

2016

J Steroids Horm Sci

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Introduction of α, β-unsaturated ketones to ∆ 5 steroidal olefins changes the characteristics and biological function of those compounds. Several synthetic methods have been reported to accomplish carbonyl introduction to ∆ 5 steroidal olefins. Herein, this short review will catalogue many of those oxidative methods, particularly those proceeding through a peroxide intermediate and/or use chromium complexes as reagents. to undesired side products, one in particular being C25 for steroids with side chains [15]. Furthermore, cleavage of the side chain can occur concurrent with allylic oxidation [16].Protecting the C3 hydroxy group is commonly accomplish by esterification using acetic anhydride to make cholesteryl acetate. The authors of this review prefer esterification with benzoyl chloride since cholesteryl benzoate products can be more easily isolated with recrystallization in acetone and water than the steroidal acetates. This esterification is necessary because many oxidants and catalysts will convert the C3 hydroxyl group to a ketone [17].Due to interest in "green" or environmentally benign chemistry, chemists have questioned the ethics of earlier catalysts. Environmental and health concerns have motivated the search for new oxidants and catalysts [18]. From chromium based catalysts, the next phase in steroidal allylic oxidation manifested through more environmentally friendly metallic catalysts that use TBHP as an oxygen donor. Meanwhile, several methods have been reported to give steroidal oxidation without any metal catalysts using as sodium chlorite and sodium hypochlorite [19,20]. Additionally, recoverable heterogeneous catalysts, clay

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Importance of cholesterol and oxysterols metabolism in the pharmacology of tamoxifen and other AEBS ligands

Cited by 52 publications

References 37 publications

4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy

4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy

Guidelines for the use and interpretation of assays for monitoring autophagy

A Short Review of Methods for the Allylic Oxidation of Δ5 Steroidal Compounds to Enones

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