Activation of specific RXR heterodimers by an antagonist of RXR homodimers

Lala, Deepak S.; Mukherjee, Ranjan; Schulman, Ira G.; Koch, Stacie S. Canan; Dardashti, L. J.; Nadzan, Alex M.; Croston, Glenn; Evans, Ronald M.; Heyman, Richard A.

doi:10.1038/383450a0

Cited by 162 publications

(169 citation statements)

References 28 publications

Supporting

Mentioning

158

Contrasting

Unclassified

Order By: Relevance

“…At a 100 : 1 molar ratio relative to the two natural retinoids, the RXR antagonist CD3159 30 does not have any appreciable effect on the growth arrest induced by ATRA, whereas it inhibits by approximately 50% the anti-proliferative action of 9-cis RA ( Figure 3D). At both 10 : 1 and 100 : 1 molar ratio, CD3159 lowers by approximately 20% the induction of NBT-reducing activity caused by 9-cis RA, while exerting only marginal effects on the ATRA-dependent elevation of the same enzymatic activity ( Figure 3E).…”

Section: Resultsmentioning

confidence: 99%

“…The RARa agonist AM580, 10 the RARb agonist CD2019, 28 the RXR agonists CD2809 and CD2915, 29 the anti-AP1 retinoid CD2409, the pan-RAR reverse agonist CD3106 (AGN193109) 46 and the pan-RXR antagonist CD3159 (LG100754) 30 were synthesized by CIRDGalderma Research and Development (Sophia Antipolis, France). The pan-RAR agonist TTNPB 27 was a kind gift from Dr. Klaus (Hoffmann-la Roche, Basel, Switzerland).…”

Section: Chemicalsmentioning

confidence: 99%

See 1 more Smart Citation

Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

et al. 2000

View full text Add to dashboard Cite

In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARaselective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARb agonist and an anti-AP1 retinoid have very limited activity, ATRA-and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARa. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD. Cell Death and Differentiation (2000) 7, 447 ± 460.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

et al. 2000

View full text Add to dashboard Cite

show abstract

“…AP-1 is a rather ubiquitous inflammatory transcription factor, and it is responsible for the regulation of a large number of genes, including MMP-3, which were unaffected by LG268 treatment. Previous studies characterizing LG268 (41)(42)(43) indicated that treatment with this rexinoid activates a limited number of RXR-containing NHR dimers, including RXR-RXR, RXR-farnesoid X receptor, RXR-liver X receptor, RXR-peroxisome proliferator-activated receptor ␣ [PPAR␣], and RXR-PPAR␥. In reviewing the literature, we found substantial data linking specific ligands for PPAR␥ to inhibition of MMP production and therapeutic activity in models of arthritis (44)(45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Burrage¹,

Huntington²,

Sporn³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To evaluate the effects of LG100268 (LG268), a synthetic ligand for the nuclear hormone receptor retinoid X receptor, on the expression of matrix metalloproteinase 1 (MMP-1) and MMP-13 induced by proinflammatory cytokines in a chondrocyte model.Methods. SW-1353 human chondrosarcoma cells were used to study the effects of LG268 on interleukin-1␤ (IL-1␤)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcriptionpolymerase chain reaction, and protein levels were determined by Western blot analysis. Collagen degradation was determined by an in vitro matrix destruction assay. The effects of LG268 on nuclear protein binding and histone acetylation were determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively.Results.LG268 treatment specifically antagonized the IL-1␤-mediated induction of MMP-1 and MMP-13 heterogeneous nuclear RNA, messenger RNA, and protein. The inhibitory effect of LG268 was found to be due to a decrease in the rate of MMP-1 and MMP-13 transcription.LG268 treatment also prevented the in vitro degradation of a type I collagen matrix by IL-1␤-treated SW-1353 cells. The inhibitory effect of LG268 on MMP-1 and MMP-13 transcription appears to be mediated, at least in part, through modulation of histone modification in regions of the MMP-1 and MMP-13 promoters that contain binding sites for activator protein 1 transcription factors.Conclusion. These data indicate that LG268 treatment selectively inhibits inflammatory cytokineinduced production of MMP-1 and MMP-13 at the level of gene transcription and blocks collagen destruction by proinflammatory cytokine-stimulated chondrocytic cells. This study is among the first to describe how rexinoids affect gene expression, and the findings suggest that the rexinoid class of compounds may have a future role in preventing the irreversible collagen destruction seen in the arthritides.The destruction of joint tissues that is a hallmark of rheumatoid arthritis (RA) and osteoarthritis (OA) is mediated largely by members of the matrix metalloproteinase (MMP) family of enzymes (1-3). At low expression levels, these zinc-dependent endopeptidases maintain connective tissue homeostasis in a wide range of biologic functions (4). However, abnormally high levels of MMP expression have been linked to multiple pathologic states, including tumor invasion, atherosclerosis, and the arthritides (4). In humans, the MMP family currently encompasses 23 unique members, which degrade all constituents of the extracellular matrix (ECM) (5). The MMPs can be subdivided into 6 main classes (1,4,5), consisting of the collagenases (MMPs 1, 8, and 13), the gelatinases (MMPs 2 and 9), the stromelysins (MMPs 3, 10, and 11), the matrilysins (MMPs 7 and 26), the membrane-type MMPs (MMPs 14,15,16,17,24,and 25), and a diverse subgroup.The collagenase subgroup is unique in its ability to cleave fibrillar collagens, and their enzymatic activity represents a rate-limiting step...

show abstract

“…Because PPAR␥ activity depends on heterodimerization with RXR␣, it is possible that modulation of PPAR␥ and degradation by R-etodolac is mediated by its binding to RXR␣. Antagonists of RXR homodimers are known to function as agonists of RXR͞PPAR␥ heterodimers (36,37).…”

Section: Discussionmentioning

confidence: 99%

The R -enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis

Kolluri

Corr

James

et al. 2005

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

View full text Add to dashboard Cite

Prostate cancer is often slowly progressive, and it can be difficult to treat with conventional cytotoxic drugs. Nonsteroidal antiinflammatory drugs inhibit the development of prostate cancer, but the mechanism of chemoprevention is unknown. Here, we show that the R-enantiomer of the nonsteroidal antiinflammatory drug etodolac inhibited tumor development and metastasis in the transgenic mouse adenocarcinoma of the prostate (TRAMP) model, by selective induction of apoptosis in the tumor cells. This proapoptotic effect was associated with loss of the retinoid X receptor (RXR␣) protein in the adenocarcinoma cells, but not in normal prostatic epithelium. R-etodolac specifically bound recombinant RXR␣, inhibited RXR␣ transcriptional activity, and induced its degradation by a ubiquitin and proteasome-dependent pathway. The apoptotic effect of R-etodolac could be controlled by manipulating cellular RXR␣ levels. These results document that pharmacologic antagonism of RXR␣ transactivation is achievable and can have profound inhibitory effects in cancer development.cancer ͉ prostate ͉ R-etodolac ͉ ubiquitin ͉ chemoprevention S everal epidemiological studies have shown that the use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a reduced incidence of clinically detectable prostate cancer (1-3). The side effects of cyclooxygenase (COX) inhibitors preclude the use of these agents in many elderly men (4). Thus, there is a major need to determine whether there are chemopreventative, and antimetastatic effects of NSAIDs that can be separated from COX inhibition. Controversy has permeated this field, because many of the COX-independent actions of NSAIDs are measurable only at concentrations that are not safely achievable in vivo, and because the members of this structurally diverse group of drugs are metabolized extensively and can exert different mechanisms of action (5, 6).Various NSAIDs have been demonstrated to induce apoptosis in malignant cells (7-9). Etodolac is a commercially available NSAID containing a racemic mixture, in which the S-enantiomer has COX inhibitory activity, whereas the R-enantiomer does not (10). Unlike all other chiral NSAIDs, the two enantiomers of etodolac are not metabolically interconvertible. Moreover, the R-enantiomer is metabolized much more slowly than the S-enantiomer, and it accumulates to 10-fold higher concentrations than the S-enantiomer in plasma (11). In a recent study, sufficient plasma levels of R-etodolac were achieved after oral gavage in a xenograft prostate cancer model to diminish the growth of the transplanted tumor (12).The in vivo effect of R-etodolac was associated with enhancement of peroxisome proliferator-activated receptor ␥ (PPAR␥) transactivation (12). PPAR␥, as well as other nuclear hormone receptors, forms heterodimers with the retinoid X receptor ␣ (RXR␣) (13,14), which has been implicated in the pathogenesis of prostate cancer (15). The effect of RXR␣ may be due to its induction of apoptosis through its interaction with other proteins (16)(17)(18)...

show abstract

Activation of specific RXR heterodimers by an antagonist of RXR homodimers

Cited by 162 publications

References 28 publications

Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

The R -enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis

Contact Info

Product

Resources

About