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2000
Volume 17, Issue 3
  • ISSN: 2589-9775
  • E-ISSN: 2589-9783

Abstract

The Retinoid X Receptor (RXR) is a member of the nuclear receptor superfamily and regulates gene transcription as well as diverse cellular processes like metabolism, inflammation, and cell differentiation. As an attractive therapeutic target, RXR inhibitors have garnered attention for their potential in alleviating chronic diseases. RXR inhibitors have the potential to modulate inflammation and immune responses and manage diseases like rheumatoid arthritis, inflammatory diseases, metabolic disorders such as diabetes and dyslipidemia, cancer progression, solid tumors, and hematologic malignancies. Understanding the molecular mechanisms behind their therapeutic effects is crucial for optimizing their use in different disease contexts. While RXR inhibitors hold promise, some challenges and questions necessitate further research. Future directions include refining the understanding of specific pathways affected by RXR inhibition and addressing potential side effects along with tailoring treatment approaches based on individual patient characteristics, as this would improve outcomes. Exploring the potential synergies of RXR inhibitors with other therapeutic agents could enhance their efficacy and broaden their applicability.

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References

  1. de AlmeidaN.R. Conda-SheridanM. A review of the molecular design and biological activities of RXR agonists.Med. Res. Rev.20193941372139730941786
     [Google Scholar]
  2. ShaoM. LuL. WangQ. MaL. TianX. LiC. LiC. GuoD. WangQ. WangW. WangY. The multi-faceted role of retinoid X receptor in cardiovascular diseases.Biomed. Pharmacother.202113711126433761589
     [Google Scholar]
  3. Saito-HakodaA. UrunoA. YokoyamaA. ShimizuK. ParvinR. KudoM. Saito-ItoT. SatoI. KogureN. SuzukiD. ShimadaH. YoshikawaT. FujiwaraI. KagechikaH. IwasakiY. KureS. ItoS. SugawaraA. Effects of RXR agonists on cell proliferation/apoptosis and ACTH secretion/Pomc expression.PLoS One20151012e014196026714014
     [Google Scholar]
  4. Domínguez-AvilaJ.A. Dietary Phenolic Compounds Exert Some of Their Health-Promoting Bioactivities by Targeting Liver X Receptor (LXR) and Retinoid X Receptor (RXR).Foods20231223420510.3390/foods1223420538231664
     [Google Scholar]
  5. le MaireA. TeyssierC. BalaguerP. BourguetW. GermainP. Regulation of RXR-RAR heterodimers by RXR-and RAR-specific ligands and their combinations.Cells2019811139231694317
     [Google Scholar]
  6. SharmaS. ShenT. ChitranshiN. GuptaV. BasavarajappaD. SarkarS. MirzaeiM. YouY. KrezelW. GrahamS.L. GuptaV. Retinoid X receptor: cellular and biochemical roles of nuclear receptor with a focus on neuropathological involvement.Mol. Neurobiol.20225942027205010.1007/s12035‑021‑02709‑y35015251
     [Google Scholar]
  7. YamadaS. KakutaH. Retinoid X receptor ligands: a patent review (2007 – 2013).Expert Opin. Ther. Pat.201424444345210.1517/13543776.2014.88069224456080
     [Google Scholar]
  8. DawsonM.I. XiaZ. The retinoid X receptors and their ligands.Biochim. Biophys. Acta Mol. Cell Biol. Lipids201218211215610.1016/j.bbalip.2011.09.01422020178
     [Google Scholar]
  9. SchierleS. MerkD. Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents.Expert Opin. Ther. Pat.201929860562110.1080/13543776.2019.164332231298602
     [Google Scholar]
  10. Sánchez-MartínezR. ZambranoA. CastilloA.I. ArandaA. Vitamin D-dependent recruitment of corepressors to vitamin D/retinoid X receptor heterodimers.Mol. Cell. Biol.200828113817382910.1128/MCB.01909‑0718362166
     [Google Scholar]
  11. AltucciL. LeibowitzM.D. OgilvieK.M. de LeraA.R. GronemeyerH. RAR and RXR modulation in cancer and metabolic disease.Nat. Rev. Drug Discov.200761079381010.1038/nrd239717906642
     [Google Scholar]
  12. GarattiniE. GianniM. TeraoM. Retinoids as differentiating agents in oncology: a network of interactions with intracellular pathways as the basis for rational therapeutic combinations.Curr. Pharm. Des.200713131375140010.2174/13816120778061878617506722
     [Google Scholar]
  13. TakahashiB. OhtaK. KawachiE. FukasawaH. HashimotoY. KagechikaH. Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions.J. Med. Chem.200245163327333010.1021/jm025532012139443
     [Google Scholar]
  14. PérezE. BourguetW. GronemeyerH. de LeraA.R. Modulation of RXR function through ligand design.Biochim. Biophys. Acta Mol. Cell Biol. Lipids201218211576910.1016/j.bbalip.2011.04.00321515403
     [Google Scholar]
  15. LinC.Y. GustafssonJ.Å. Targeting liver X receptors in cancer therapeutics.Nat. Rev. Cancer201515421622410.1038/nrc391225786697
     [Google Scholar]
  16. FesslerMBJP The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory diseasePharmacol Ther2018181112
     [Google Scholar]
  17. XuP. LiD. TangX. BaoX. HuangJ. TangY. YangY. XuH. FanX. LXR agonists: new potential therapeutic drug for neurodegenerative diseases.Mol. Neurobiol.201348371572810.1007/s12035‑013‑8461‑323625315
     [Google Scholar]
  18. NakayamaM. YamadaS. OhsawaF. OhtaY. KawataK. MakishimaM. KakutaH. Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.ACS Med. Chem. Lett.201121289690010.1021/ml200197e24900278
     [Google Scholar]
  19. ZhouH. LiuW. SuY. WeiZ. LiuJ. KolluriS.K. WuH. CaoY. ChenJ. WuY. YanT. CaoX. GaoW. MolotkovA. JiangF. LiW.G. LinB. ZhangH.P. YuJ. LuoS.P. ZengJ.Z. DuesterG. HuangP.Q. ZhangX.K. NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.Cancer Cell201017656057310.1016/j.ccr.2010.04.02320541701
     [Google Scholar]
  20. SakakiJ. KonishiK. KishidaM. GunjiH. KanazawaT. UchiyamaH. FukayaH. MitaniH. KimuraM. Synthesis and structure–activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure.Bioorg. Med. Chem. Lett.200717174808481110.1016/j.bmcl.2007.06.07917651969
     [Google Scholar]
  21. UmemiyaH. FukasawaH. EbisawaM. EyrollesL. KawachiE. EisenmannG. GronemeyerH. HashimotoY. ShudoK. KagechikaH. Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.J. Med. Chem.199740264222423410.1021/jm97043099435893
     [Google Scholar]
  22. SantínE.P. GermainP. QuillardF. KhanwalkarH. Rodríguez-BarriosF. GronemeyerH. de LeraÁ.R. BourguetW. Modulating retinoid X receptor with a series of (E)-3-[4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers.J. Med. Chem.200952103150315810.1021/jm900096q19408900
     [Google Scholar]
  23. ChaiSC WrightWC Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancerMed Res Rev202040310611083
     [Google Scholar]
  24. KoyamaE. MundyC. SaundersC. ChungJ. CathelineS.E. RuxD. IwamotoM. PacificiM. Premature Growth Plate Closure Caused by a Hedgehog Cancer Drug Is Preventable by Co-Administration of a Retinoid Antagonist in Mice.J. Bone Miner. Res.20203671387140210.1002/jbmr.429133724538
     [Google Scholar]
  25. ViragovaS. AparicioL. PalmeriniP. ZhaoJ. Valencia SalazarL.E. SchurerA. DhuriA. SahooD. MoskalukC.A. RabadanR. DalerbaP. Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma.J. Natl. Cancer Inst.2023115783885210.1093/jnci/djad06237040084
     [Google Scholar]
  26. WaizeneggerJ. LenzeD. LuckertC. SeidelA. LampenA. HesselS. Dose‐dependent induction of signaling pathways by the flavonoid quercetin in human primary hepatocytes: A transcriptomic study.Mol. Nutr. Food Res.20155961117112910.1002/mnfr.20140076425788151
     [Google Scholar]
  27. HaoX. XiaoH. JuJ. LeeM.J. LambertJ.D. YangC.S. Green tea polyphenols inhibit colorectal tumorigenesis in azoxymethane-treated F344 rats.Nutr. Cancer201769462363110.1080/01635581.2017.129508828323438
     [Google Scholar]
  28. MajE. MajB. BobakK. GosM. ChodyńskiM. KutnerA. WietrzykJ. Differential response of lung cancer cells, with various driver mutations, to plant polyphenol resveratrol and vitamin D active metabolite PRI-2191.Int. J. Mol. Sci.2021225235410.3390/ijms2205235433652978
     [Google Scholar]
  29. XieC.L. ZhangD. GuoK.Q. YanQ.X. ZouZ.B. HeZ.H. WuZ. ZhangX-K. ChenH-F. YangX-W. Meroterpenthiazole A, a unique meroterpenoid from the deep-sea-derived Penicillium allii-sativi, significantly inhibited retinoid X receptor (RXR)-α transcriptional effect.Chin. Chem. Lett.20223342057205910.1016/j.cclet.2021.09.073
     [Google Scholar]
  30. WuY. LiaoH. LiuL.Y. SunF. ChenH.F. JiaoW.H. ZhuH.R. YangF. HuangG. ZengD.Q. ZhouM. WangS.P. LinH.W. Phakefustatins A–C: Kynurenine-bearing cycloheptapeptides as RXRα modulators from the marine sponge Phakellia fusca.Org. Lett.202022176703670810.1021/acs.orglett.0c0158632701300
     [Google Scholar]
  31. GrubbsCJ HillDL BlandKI BeenkenSW LinT-H EtoI 9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancersCancer Lett200320111724
     [Google Scholar]
  32. MazumdarA. MedinaD. KittrellF.S. ZhangY. HillJ.L. EdwardsD.E. BissonnetteR.P. BrownP.H. The combination of tamoxifen and the rexinoid LG100268 prevents ER-positive and ER-negative mammary tumors in p53-null mammary gland mice.Cancer Prev. Res. (Phila.)20125101195120210.1158/1940‑6207.CAPR‑11‑052422926341
     [Google Scholar]
  33. WuJ. WangX. ZhangM. MathewsP. KangY. RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect.Cells20231215199310.3390/cells1215199337566072
     [Google Scholar]
  34. BrownP.H. SubbaramaiahK. SalmonA.P. BakerR. NewmanR.A. YangP. ZhouX.K. BissonnetteR.P. DannenbergA.J. HoweL.R. Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid.Cancer Prev. Res. (Phila.)20081320821410.1158/1940‑6207.CAPR‑08‑002119138958
     [Google Scholar]
  35. KongJ.N. HeQ. WangG. DasguptaS. DinkinsM.B. ZhuG. KimA. SpassievaS. BieberichE. Guggulsterone and bexarotene induce secretion of exosome‐associated breast cancer resistance protein and reduce doxorubicin resistance in MDA‐MB ‐231 cells.Int. J. Cancer201513771610162010.1002/ijc.2954225833198
     [Google Scholar]
  36. PlutzkyJ. The PPAR-RXR transcriptional complex in the vasculature: energy in the balance.Circ. Res.201110881002101610.1161/CIRCRESAHA.110.22686021493923
     [Google Scholar]
  37. DesvergneB. RXR: from partnership to leadership in metabolic regulations.Vitam. Horm.20077513210.1016/S0083‑6729(06)75001‑417368310
     [Google Scholar]
  38. SherrattS.C.R. LibbyP. BudoffM.J. BhattD.L. MasonR.P. Role of omega-3 fatty acids in cardiovascular disease: the debate continues.Curr. Atheroscler. Rep.202325111710.1007/s11883‑022‑01075‑x36580204
     [Google Scholar]
  39. DheerY. Understanding the Retinoid-x-receptor biology and manipulating it as a novel strategy to protect the retina.2022
     [Google Scholar]
  40. AtigaddaV.R. KashyapM.P. YangZ. ChattopadhyayD. MeloN. SinhaR. BelyaevaO.V. ChouC.F. ChangP.L. KedishviliN.Y. GrubbsC.J. RenfrowM.B. MuccioD.D. ElmetsC.A. AtharM. Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers.J. Med. Chem.20226521144091442310.1021/acs.jmedchem.2c0073536318154
     [Google Scholar]
  41. SzymańskiŁ. SkopekR. PalusińskaM. SchenkT. StengelS. LewickiS. KrajL. KamińskiP. ZelentA. Retinoic acid and its derivatives in skin.Cells2020912266010.3390/cells912266033322246
     [Google Scholar]
  42. DaiX. JinJ. JiaY. YangK. HanJ. ZhangZ. DingX. YaoC. SunT. ZhuC. LiuH. A non‐retinol retinoic acid receptor‐γ (RAR‐γ/NR1B3) selective agonist, tectorigenin, can effectively inhibit the ultraviolet A‐induced skin damage.Br. J. Pharmacol.2022179194722473710.1111/bph.1590235731978
     [Google Scholar]
  43. SchierleS. ChaikuadA. LillichF.F. NiX. WoltersdorfS. SchallmayerE. ReneltB. RonchettiR. KnappS. ProschakE. MerkD. Oxaprozin analogues as selective RXR agonists with superior properties and pharmacokinetics.J. Med. Chem.20216485123513610.1021/acs.jmedchem.1c0023533793232
     [Google Scholar]
  44. ZhaoL. LeiW. DengC. WuZ. SunM. JinZ. SongY. YangZ. JiangS. ShenM. YangY. The roles of liver X receptor α in inflammation and inflammation‐associated diseases.J. Cell. Physiol.202123674807482810.1002/jcp.3020433305467
     [Google Scholar]
  45. LealA.S. ReichL.A. MoerlandJ.A. ZhangD. LibyK.T. Potential therapeutic uses of rexinoids.Adv. Pharmacol.20219114118310.1016/bs.apha.2021.01.00434099107
     [Google Scholar]
  46. ClarkJ.N. WhitingA. McCafferyP. Retinoic acid receptor-targeted drugs in neurodegenerative disease.Expert Opin. Drug Metab. Toxicol.202016111097110810.1080/17425255.2020.181123232799572
     [Google Scholar]
  47. WishartD.S. FeunangY.D. GuoA.C. LoE.J. MarcuA. GrantJ.R. SajedT. JohnsonD. LiC. SayeedaZ. AssempourN. IynkkaranI. LiuY. MaciejewskiA. GaleN. WilsonA. ChinL. CummingsR. LeD. PonA. KnoxC. WilsonM. DrugBank 5.0: a major update to the DrugBank database for 2018.Nucleic Acids Res.201846D1D1074D108210.1093/nar/gkx103729126136
     [Google Scholar]
  48. OyarceC. Vizcaino-CastroA. ChenS. BoermaA. DaemenT. Re-polarization of immunosuppressive macrophages to tumor-cytotoxic macrophages by repurposed metabolic drugs.OncoImmunology2021101189875310.1080/2162402X.2021.189875333796407
     [Google Scholar]
  49. SunS. PengK. YangB. YangM. JiaX. WangN. ZhangQ. KongD. DuY. The therapeutic effect of wine-processed Corni Fructus on chronic renal failure in rats through the interference with the LPS/IL-1-mediated inhibition of RXR function.J. Ethnopharmacol.202432111751110.1016/j.jep.2023.11751138036016
     [Google Scholar]
  50. ZhaoW LiS ChenR NiJ HuangX LiS RXR signaling targeted cancer therapy.20231110001410.59717/j.xinn‑life.2023.100014
     [Google Scholar]
  51. YeX. WuH. ShengL. LiuY. YeF. WangM. ZhouH. SuY. ZhangX. Oncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling.Nat. Commun.2019101146310.1038/s41467‑019‑09375‑830931933
     [Google Scholar]
  52. WangJ. XueX. ZhaoX. LuoL. LiuJ. DaiS. Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-gamma/RXR-alpha complex.J. Adv. Res.202310.1016/j.jare.2023.08.00637579917
     [Google Scholar]
  53. WangY. ZhaoH. LinC. RenJ. ZhangS. ForsythiasideA. Forsythiaside A Exhibits Anti-inflammatory Effects in LPS-Stimulated BV2 Microglia Cells Through Activation of Nrf2/HO-1 Signaling Pathway.Neurochem. Res.201641465966510.1007/s11064‑015‑1731‑x26498935
     [Google Scholar]
  54. WuM. WangJ. ZhouW. WangM. HuC. ZhouM. JiaoK. LiZ. Vitamin D inhibits tamoxifen-induced non-alcoholic fatty liver disease through a nonclassical estrogen receptor/liver X receptor pathway.Chem. Biol. Interact.202438911086510.1016/j.cbi.2024.11086538191086
     [Google Scholar]
  55. LvM. ShiX-l. LiW. ZhouM. GouX. HuangY. Daqinjiao Decoction Ameliorates CSVD Induced by Chronic Cerebral Hypoperfusion in Rats via Activating the PPAR Signaling Pathway: Insights from Transcriptome Sequencing and Network Pharmacology.SSRN202410.2139/ssrn.4670812
     [Google Scholar]
  56. CroweD.L. ChandraratnaR.A.S. A retinoid X receptor (RXR)-selective retinoid reveals that RXR-α is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands.Breast Cancer Res.200465R546R55510.1186/bcr91315318936
     [Google Scholar]
  57. LeeJ.J. WuX. HildebrandtM.A.T. YangH. KhuriF.R. KimE. GuJ. YeY. LotanR. SpitzM.R. HongW.K. Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients.Cancer Prev. Res. (Phila.)20114218519310.1158/1940‑6207.CAPR‑10‑012521292633
     [Google Scholar]
  58. TalpurR. WardS. ApisarnthanaraxN. Breuer-McHamJ. DuvicM. Optimizing bexarotene therapy for cutaneous T-cell lymphoma.J. Am. Acad. Dermatol.200247567268410.1067/mjd.2002.12460712399758
     [Google Scholar]
  59. BrownP.H. SubbaramaiahK. SalmonA.P. BakerR. NewmanR.A. YangP. Combination chemoprevention of HER2/neu-induced breast cancer using a COX-2 inhibitor and an RXR-selective retinoid.Cancer Prev. Res. (Phila.)20081320810.1158/1940‑6207.CAPR‑08‑002119138958
     [Google Scholar]
  60. BrownPHJCEB Preclinical and clinical studies for the prevention of ER-negative breast cancer.Cancer Epidemiol Biomarkers Prev20061512_SupplementCS09CS04
     [Google Scholar]
  61. LiB. CaiS.Y. BoyerJ.L. The role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology.Biochim. Biophys. Acta Mol. Basis Dis.20211867516608510.1016/j.bbadis.2021.16608533497820
     [Google Scholar]
  62. DengK. RenC. FanY. LiuZ. ZhangG. ZhangY. YouP. WangF. miR-27a is an important adipogenesis regulator associated with differential lipid accumulation between intramuscular and subcutaneous adipose tissues of sheep.Domest. Anim. Endocrinol.20207110639310.1016/j.domaniend.2019.10639331731253
     [Google Scholar]
  63. RaoM. McDuffieE. SrivastavaS. PlaistedW. SachsC. Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives.Pharmaceuticals (Basel)202417787510.3390/ph1707087539065726
     [Google Scholar]
  64. Vivat-HannahV Retinoids as therapeutic agents: Today and tomorrowMini Rev Med Chem200558755760
     [Google Scholar]
  65. ZhuL. LuL. WangS. WuJ. ShiJ. YanT. Oral absorption basics: pathways and physicochemical and biological factors affecting absorption.Developing solid oral dosage forms.201729732910.1016/B978‑0‑12‑802447‑8.00011‑X
     [Google Scholar]
  66. PrakashC. ZunigaB. Seog SongC. JiangS. CropperJ. ParkS. ChatterjeeB. Nuclear receptors in drug metabolism, drug response and drug interactions.Nucl. Receptor Res.20152210.11131/2015/10117827478824
     [Google Scholar]
  67. JosephC. Al-IzziS. AlsaleemM. KurozumiS. TossM.S. ArshadM. GohF.Q. AlshankytyI.M. AleskandaranyM.A. AliS. EllisI.O. MonganN.P. GreenA.R. RakhaE.A. Retinoid X receptor gamma (RXRG) is an independent prognostic biomarker in ER-positive invasive breast cancer.Br. J. Cancer2019121977678510.1038/s41416‑019‑0589‑031558802
     [Google Scholar]
  68. HandelmanS.K. PuentesY.M. KuppaA. ChenY. DuX. FeitosaM.F. PalmerN.D. SpeliotesE.K. Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids.Hepatol. Commun.20226113120313110.1002/hep4.206636098472
     [Google Scholar]
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A Narrative Overview of Retinoid X Receptor Inhibitors in Chronic Disease Management
Current Drug Research Reviews 17, 333 (2025); https://doi.org/10.2174/0125899775314743241111063341
/content/journals/cdrr/10.2174/0125899775314743241111063341
/content/journals/cdrr/10.2174/0125899775314743241111063341
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  • Article Type:     Review Article
Keyword(s): cancer; chronic disease management; diabetes; inflammation; RXR inhibitor; therapeutic agents

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