Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3

Boehm, Marcus F.; Fitzgerald, Patrick; Zou, Aihua; Elgort, Marc G.; Bischoff, Eric D.; Mere, Lora; Mais, Dale E.; Bissonnette, Reid P.; Heyman, Richard A.; Nadzan, Alex M.; Reichman, Melvin; Allegretto, Elizabeth A.

doi:10.1016/s1074-5521(99)80072-6

Cited by 146 publications

(118 citation statements)

References 28 publications

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“…This phenomenon has been observed in the case of vitamin D receptor (VDR) ligands, where potent VDR agonists did not displace radiolabeled 1,25-dihydroxyvitamin D3 because of its high K on and low K off for the receptor (Boehm et al, 1999;Ma et al, 2006). Our biochemical AlphaScreen-based assays using purified LXR␣ and ␤ LBD proteins and synthetic cofactor LXXLL motif peptide (SRC-2 NR box III) clearly demonstrate that 5,6-EC is bona fide ligand of both LXR␣ and ␤ subtypes, with at least a single-digit micromolar potency (Fig.…”

Section: Abca1 Abcg1mentioning

confidence: 87%

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Berrodin¹,

Shen²,

Quinet³

et al. 2010

Mol Pharmacol

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The liver X receptors (LXR␣ and LXR␤) are members of the nuclear receptor superfamily that function as key transcriptional regulators of a number of biological processes, including cholesterol homeostasis, lipid metabolism, and keratinocyte differentiation. Natural ligands that activate LXRs include oxysterol derivatives such as 25-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, 20(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Related oxysterols, such as 5␣,6␣-epoxycholesterol (5,6-EC) are present in a number of foods and have been shown to induce atherosclerosis in animal models. Intriguingly, these oxysterols have also been detected in atherosclerotic plaques. Using a variety of biochemical and cellular assays, we demonstrate that 5,6-EC is the first dietary modulator and an endogenous LXR ligand with cell and gene context-dependent antagonist, agonist, and inverse agonist activities. In a multiplexed LXR-cofactor peptide interaction assay, 5,6-EC induced the recruitment of a number of cofactor peptides onto both LXR␣ and LXR␤ and showed an EC 50 of approximately 2 M in peptide recruitment. Furthermore, 5,6-EC bound to LXR␣ in a radiolabeled ligand displacement assay (EC 50 ϭ 76 nM), thus demonstrating it to be one of the most potent natural LXR␣ ligands known to date. Analysis of endogenous gene expression in various cell-based systems indicated the potential of 5,6-EC to antagonize LXR-mediated gene expression. Furthermore, it also induced the expression of some LXR-responsive genes in keratinocytes. These results clearly demonstrate that 5,6-EC is an LXR modulator that may play a role in the development of lipid disorders, such as atherosclerosis, by antagonizing the agonistic action of endogenous LXR ligands.

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Section: Abca1 Abcg1mentioning

confidence: 87%

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Berrodin¹,

Shen²,

Quinet³

et al. 2010

Mol Pharmacol

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“…This cell context-selective action translated into reduced hypercalcemia in vivo in comparison with 1,25-(OH) 2 D 3 when mice were treated orally or topically with the VDRMs LY2108491 and LY2109866 ( Figures 9 and 11 and Table 1). Although nonsecosteroidal and nonsteroidal VDR ligands have been described (24,38,39), they have not been shown to act as a modulator in a cell context-dependent manner. Recently, a tissue-and cell type-selective secosteroidal VDRM (Ro-26-9228) has been described (40).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators

Khalifa²,

Yee³

et al. 2006

Journal of Clinical Investigation

108

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Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ] in an in vivo preclinical surrogate model of psoriasis.

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“…EB1089 effectively inhibits the growth of LNCaP cells, exhibits greater potency than 1,25(OH) 2 D 3 (Skowronski et al, 1995), and is only 50% as calcemic in vivo (Hansen and Maenpaa, 1997;Kissmeyer et al, 1997). Other analogs, including 16-diene analogs (Schwartz et al, 1994;Hedlund et al, 1997), 1,25 dihydroxy-16-ene-23-yne-vitamin D 3 (Schwartz et al, 1995), 19-nor-hexafluoride D 3 analogs (Campbell et al, 1997), 19-nor-26,27-bishomo-vitamin D 3 analogs (Kubota et al, 1998), 20-cyclopropyl-cholecalciferol vitamin D 3 (Koike et al, 1999), 5,6-trans-16-ene-vitamin D 3 (Hisatake et al, 1999), and some nonsecosteroidal analogs (Boehm et al, 1999) also inhibit the growth of prostate cancer cells in vitro. Interestingly, some analogs inhibit the growth of the 1,25(OH) 2 D 3 resistant DU145 cells (Schwartz et al, 1994;Kubota et al, 1998;Koike et al, 1999), and it has been suggested that DU145 resistance to 1,25(OH) 2 D 3 is due to the rapid metabolism of 1,25(OH) 2 D 3 by 24-hydroxylase in these cells (Ly et al, 1999).…”

Section: Vitamin D Analogsmentioning

confidence: 99%

Vitamin D and Prostate Cancer

Polek

Weigel

2002

Journal of Andrology

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Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American men. It arises primarily from the epithelial secretory cells of the peripheral prostate gland; generally occurs as a multifocal disease within the prostate gland; and then preferentially metastasizes to lymph nodes, bone, lung, and brain. Localized disease can be treated relatively successfully by radical prostatectomy (Catalona and Smith, 1998). In contrast, treatments for metastatic prostate cancer, including androgen ablation, are initially effective, but the majority of patients relapse with androgen independent prostate cancer (Denis, 1998; Leewansangtong and Crawford, 1998). The incidence of prostate cancer and the lack of good, long-term treatments for metastatic disease highlight the need for new chemopreventive and chemotherapeutic treatments. As discussed below, active vitamin D metabolites and analogs of the active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), are candidates for these treatments. Vitamin DVitamin D is best known for its actions in regulating calcium levels and bone remodeling (reviewed in Brown et al, 1999), but recent studies highlight a role for vitamin D in the growth and differentiation of various cell types. It is synthesized in the epidermis by the conversion of its precursor, 7-dehydrocholesterol, into vitamin D 3 , a reaction catalyzed by the ultraviolet rays of sunlight. Subsequent hydroxylation reactions in the liver and kidney produce 1,25(OH) 2 D 3 (Holick, 1984). Levels of 1,25(OH) 2 D 3 are tightly regulated as excess 1,25(OH) 2 D 3 is inactivated by the enzyme 24-hydroxylase (Horst and Reinhardt, 1997).

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Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3

Abstract: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.

Cited by 146 publications

References 28 publications

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Identification of 5α,6α-Epoxycholesterol as a Novel Modulator of Liver X Receptor Activity

Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators

Vitamin D and Prostate Cancer

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