The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

Niesor, Eric J.; Flach, Jean; Lopes-Antoni, Isabelle; Perez, Anne; Bentzen, C.

doi:10.2174/1381612013398185

Cited by 46 publications

(34 citation statements)

References 98 publications

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“…As in vascular smooth muscle, FXR ligands induce apoptosis, associated with cytoplasmic DNA-chromatin complexes, DNA laddering, and caspase-3 activation in a variety of cancer cells (11). The initial , and CDCA, alone or in combination with guggulsterone (ϩG) (n ϭ 4, for each).…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic FXR ligands have been identified, including GW4064 (9), fexaramine (10), and a series of 1,1-bisphosphonate esters (11), including Apomine (SR45023A). The 1,1-bisphosphonate esters, which may be antineoplastic drugs (12), induce apoptosis in a number of cancer cell lines, and are hypocholesterolemic in cynomolgus monkeys (11).…”

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confidence: 99%

“…The 1,1-bisphosphonate esters, which may be antineoplastic drugs (12), induce apoptosis in a number of cancer cell lines, and are hypocholesterolemic in cynomolgus monkeys (11).…”

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confidence: 99%

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Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

212

163

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The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

212

163

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“…Indeed Apomine appears to fulfil these criteria: it potently stimulates HMGR degradation and in addition increases SREBP activation and LDLR activity. It should be noted that Apomine and other 1,1-bisphosphonate esters also activate the farnesoid X receptor (57,58) and the pregnane X receptor (59). The pharmacological consequences of activating these receptors by this class of compounds has yet to be investigated.…”

Section: Table IV Effect Of Apomine On Ldlr Activitymentioning

confidence: 99%

Apomine, a Novel Hypocholesterolemic Agent, Accelerates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase and Stimulates Low Density Lipoprotein Receptor Activity

Roitelman

Masson²,

Avner

et al. 2004

Journal of Biological Chemistry

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Apomine, a novel 1,1-bisphosphonate ester, has been shown to lower plasma cholesterol concentration in several species. Here we show that Apomine reduced the levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the rate-limiting enzyme in the mevalonate pathway, both in rat liver and in cultured cells. Apomine resembles sterols such as 25-hydroxycholesterol in its ability to potently accelerate the rate of HMGR degradation by the ubiquitin-proteasome pathway, a process that depends on the transmembrane domain of the enzyme. The similarity between Apomine and sterols in promoting rapid HMGR degradation extends to its acute requirements for ongoing protein synthesis and mevalonate-derived non-sterol product(s) as a co-regulator. Yet, at suboptimal concentrations, sterols potentiated the effect of Apomine in stimulating HMGR degradation, indicating that these agents act via distinct modes. Furthermore, unlike sterols, Apomine inhibited the activity of acyl-CoA:cholesterol acyltransferase in intact cells but not in cell-free extracts. Apomine stimulated the cleavage of the precursor of sterolregulatory element-binding protein-2 and increased the activity of low density lipoprotein receptor pathway. This Apomine-enhanced activation of sterol-regulatory element-binding protein-2 was prevented by sterols or mevalonate. Taken together, our results provide a molecular mechanism for the hypocholesterolemic activity of Apomine.In mammalian cells, cholesterol homeostasis is maintained by balancing cholesterol uptake and production. Cholesterol uptake is regulated through modulating the levels of the cell surface low density lipoprotein (LDL) 1 receptor (LDLR), and cholesterol synthesis is regulated primarily by changes in levels and activity of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) (1, 2). HMGR is an endoplasmic reticulum (ER) enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-CoA into mevalonate (MVA), the first committed step in the MVA pathway that leads to the synthesis of cholesterol as well as of essential non-sterol isoprenoid compounds (1, 2). When cells are starved for cholesterol and/or MVA, levels of HMGR and LDLR are elevated, thus increasing the rate of endogenous sterol synthesis and of LDL uptake (3, 4). Conversely, in cholesterol-replete cells, the levels of HMGR and LDLR decline, thereby lowering sterol production and LDL internalization.HMGR and LDLR are regulated at the transcriptional level by sterol-regulatory elements (SREs) in the promoter of their genes (1, 5). Specific transcription factors, designated SREbinding proteins (SREBPs), bind to these elements and activate transcription (5, 6). The SREBP family comprises three members that control different sets of genes. SREBP-2 regulates the transcription of genes mainly involved in sterol synthesis, whereas SREBP-1a and -1c regulate principally fatty acid biosynthetic genes (7). The nuclear, transcriptionally active SREBPs are derived from the NH 2 -terminal domain of large ER membrane-bound prec...

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“…14 However, apomine acts to down-regulate HMG-CoA reductase protein levels by increasing the proteasomal degradation rate of this enzyme. 15 Although the exact mechanisms for this are unclear, apomine appears to exert its effects by mimicking the actions of farnesol, [16][17][18] a metabolite of the mevalonate pathway intermediate farnesyl pyrophosphate, which plays a role in feedback regulation of HMG-CoA reductase activity. 19 It is interesting to note that apomine exerts antitumor activity in vitro 16,20 and in the 5T2MM mouse myeloma model 21 through mechanisms distinct from the down-regulation of HMG-CoA reductase, most likely involving inhibition of the phosphatidylcholine synthesis pathway, 18 again mimicking the actions of farnesol.…”

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Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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BACKGROUND: Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. METHODS: The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. RESULTS: Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. CONCLUSIONS: The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma. Cancer 2012;118:750-

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The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

Cited by 46 publications

References 98 publications

Expression and activation of the farnesoid X receptor in the vasculature

Expression and activation of the farnesoid X receptor in the vasculature

Apomine, a Novel Hypocholesterolemic Agent, Accelerates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase and Stimulates Low Density Lipoprotein Receptor Activity

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

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