Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

Marinozzi, Maura; Navas, Francisco Fermin Castro; Maggioni, Daniela; Carosati, Emanuele; Bocci, Giovanni; Carloncelli, Maria; Giorgi, Gianluca; Cruciani, Gabriele; Fontana, Raffaella; Russo, Vincenzo

doi:10.1021/acs.jmedchem.7b00091

Cited by 25 publications

(13 citation statements)

References 54 publications

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“…An unsaturated bond such as this makes the side chain less flexible and allows for decreased rotational freedom but may also be more prone to oxidative or enzymatic attack. A series of synthetic STIG derivatives with modifications to either the 22nd or 23rd carbon led to several compounds able to selectively modulate LXR target genes; ABCA1 expression was strongly enhanced while other canonical targets such as FASN were unaltered [38]. In subsequent work addition of a hydroxyl group at C24 to stigmastane led to robust activation of ABCA1 and FASN [39].…”

Section: Discussionmentioning

confidence: 99%

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

Hutchinson

Lianto

Moore

et al. 2019

IJMS

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Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery.

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Section: Discussionmentioning

confidence: 99%

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

Hutchinson

Lianto

Moore

et al. 2019

IJMS

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“…T0901317 enhanced the in vitro and in vivo expression of LXR target genes, including ABCA1 and ABCG1, leading to increased cholesterol efflux to apoA-I and HDL and decreased foam cell and atherosclerotic plaque formation (Fukumoto et al, 2002;Murthy et al, 2002;Terasaka et al, 2003;Thomas et al, 2003;Beyer et al, 2004;Miao et al, 2004;Quinet et al, 2004Quinet et al, , 2006Wu et al, 2004;Panzenboeck et al, 2006;Wang et al, 2006;Delvecchio et al, 2007Delvecchio et al, , 2008Fujiyoshi et al, 2007;Dai et al, 2008;DiBlasio-Smith et al, 2008;Sato et al, 2008;Zanotti et al, 2008;Larrede et al, 2009;Verschuren et al, 2009;Mogilenko et al, 2010;Morrow et al, 2010;Yan et al, 2010;Honzumi et al, 2011;Maejima et al, 2011;Chen et al, 2012;Di et al, 2012;Elali and Hermann, 2012;Jiang et al, 2012;Ma et al, 2014;Kaneko et al, 2015;Kirchgessner et al, 2015;Manna et al, 2015;Tamehiro et al, 2015;Carter et al, 2017;Jiang and Li, 2017;Marinozzi et al, 2017;Monzel et al, 201...…”

Section: B Liver X Receptor Activation To Induce Atp-binding Cassette A1 and Atp-binding Cassette G1 Expressionmentioning

confidence: 99%

“…Moreover, it amplified SREBP-1c expression leading to increased hepatic and plasma triglyceride levels (Sparrow et al, 2002;Quinet et al, 2004). Various other LXR agonists, including acetyl-podocarpic dimer, LXR-623 (i.e., also known as WAY-252623), ritonavir (i.e., an antiretroviral drug), side-chain modified sterol, ergosterol derivatives, and C24-hydoxylated stigmastane derivatives, also effectively increased ABCA1 expression (Sparrow et al, 2002;DiBlasio-Smith et al, 2008;Pou et al, 2008;Quinet et al, 2009;Marinozzi et al, 2017;Castro Navas et al, 2018). However, they all produced unwanted effects on plasma triglyceride levels by stimulation of SREBP-1c gene transcription and LXR-623 enhanced plasma triglyceride levels, yet all to a lower extent than T0901317 (Sparrow et al, 2002;DiBlasio-Smith et al, 2008;Pou et al, 2008;Quinet et al, 2009;Marinozzi et al, 2017;Castro Navas et al, 2018).…”

Section: B Liver X Receptor Activation To Induce Atp-binding Cassette A1 and Atp-binding Cassette G1 Expressionmentioning

confidence: 99%

“…Type II DNA topoisomerase inhibitors, which are used as chemotherapeutic medication, also enhanced Jiang et al, 2012;Ma et al, 2014;Kaneko et al, 2015;Kirchgessner et al, 2015;Manna et al, 2015;Tamehiro et al, 2015;Li et al, 2016;Carter et al, 2017;Jiang and Li, 2017;Marinozzi et al, 2017;Monzel et al, 2017;Kaseda et al, 2018 ↑ Murine primary macrop. Increased Cholesterol Efflux To Treat Cardiovascular Disease ABCA1 expression in an LXRa-dependent manner (Zhang et al, 2013a;Tsou et al, 2014;Shen et al, 2015).…”

Section: B Liver X Receptor Activation To Induce Atp-binding Cassette A1 and Atp-binding Cassette G1 Expressionmentioning

confidence: 99%

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Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

et al. 2019

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Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk.Significance Statement--Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment.

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“…(22R,23R)-Epoxystigmast-5-en-3β-ol (PFM009) and 23-ketostigmast-5-en-3β-ol (PFM018) (Figure 1) are two members of a small library of phytosterols derivatives characterized by the presence of oxygenated function at different position of the side-chain of ergosterol and stigmasterol. The library was designed with the aim to find LXR modulators to be specifically used as probes in cancer biology (Marinozzi et al, 2017) (Castro Navas et al, 2018. Whereas PFM009 showed high efficacy in activating both LXR isoforms, PFM018 was endowed with selectivity for the β-isoform.…”

Section: Pfm009 and Pfm018mentioning

confidence: 99%

Shedding light on the roles of liver X receptors in cancer by using chemical probes

Pontini

Marinozzi

2020

British J Pharmacology

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Nuclear receptors, liver X receptor-α (LXRα; NR1H3) and liver X receptor-β (LXRβ; NR1H2), are considered master regulators of lipid homeostasis. During the last couple of decades, their pivotal roles in several physiological and pathological processes ranging from energy supply, immunity, cardiovascular, neurodegenerative disorders and cancer have been highlighted. In this review, the main results achieved during more recent years about our understanding of the LXR involvement in cancer has been mainly obtained using small-molecule chemical probes. Remarkably, all these probes, albeit having different structure and biological properties, have a well demonstrated anti-tumoral activity arising from LXR modulation, indicating a high potential of LXR targeting for the treatment of cancer. K E Y W O R D Scancer, chemical probes, liver X receptor, small-molecules | INTRODUCTIONThanks to their molecular characteristics, nuclear receptors have proven to be a source of very favourable druggable targets. Within the superfamily most of the members classified as classical hormone receptors have become valuable therapeutic targets, even long before their discovery. As an example, the first clinical use of cortisone dates back to 1949 (Hench, Kendall, & Slocumb, 1949), whereas the human glucocorticoid receptor (NR3C1), the first one among nuclear receptors to be cloned, was identified more than 30 years later (Hollemberg et al., 1985). This event paved the way for a decade of an intensive research in the nuclear receptor field leading to the identification of many other members of this now superfamily. However, differently from the classic endocrine nuclear receptors, these newcomers lacked endogenous ligands and therefore were referred to as orphan nuclear receptors (Mazaira et al., 2018). The de-orphanization of these orphan nuclear receptor was due to the successful discovery of their endogenous ligand(s), which allows the receptor to be regarded as "adopted."Undoubtedly, the knowledge of the natural ligand is the first step towards elucidating the physiological functions of the target protein and its potential implications in certain pathological conditions. However, without the creation of high-quality small-molecule probes, our current understanding of adopted nuclear receptors could not be what it is. Moreover, the availability of chemical probes has had a major impact on enabling and improving the drug discovery process in this area. In this context, the liver X receptors (LXRs) is a case in point.Liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), which by the IUPHAR nomenclature are respectively NR1H3 and NR1H2, were discovered between 1994 and 1995 and classified as orphan receptors by different research groups

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Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

Cited by 25 publications

References 54 publications

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

Shedding light on the roles of liver X receptors in cancer by using chemical probes

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