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RAR and RXR modulation in cancer and metabolic disease

Key Points

  • Retinoic acid receptors (RARs) are ligand-controlled transcription factors that form heterodimers with rexinoid X receptors (RXRs) to regulate many physiological processes, such as embryo development and organ homeostasis.

  • The success of retinoic acid-based therapy in treating acute promyelocytic leukaemia (APL) coupled with an increased understanding in the biological roles played by RARs and RXRs has led to considerable interest in the development of RAR and RXR modulators for treating cancer.

  • Here, novel developments are described that open the possibility for drug-induced cancer cell-selective eradication. Modulation of various pathways and targets involved in cancer, including TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), p21WAF1/CIP1 and AP1 (also known as JUN), by retinoids/rexinoids have led to several clinical trials being initiated.

  • New paradigms for combination therapies are described that allow 'empowering' retinoid by signal transduction crosstalk or the combination with epigenetic drugs.

  • Recent studies on the use of rexinoids in animal models of metabolic diseases, in particular in diabetes and obesity, revealed that the actions of the RXR ligand can be distinct from that exerted by the ligand of its heterodimer partner. The perspectives for drug discovery of these novel findings are discussed.

Abstract

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. The success of RAR modulation in the treatment of acute promyelocytic leukaemia (APL) has stimulated considerable interest in the development of RAR and RXR modulators. This has been aided by recent advances in the understanding of the biological role of RARs and RXRs and in the design of selective receptor modulators that might overcome the limitations of current drugs. Here, we discuss the challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity.

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Figure 1: Building blocks for the synthesis of selective retinoic acid receptor (RAR) modulators.
Figure 2: Representative examples of retinoids exhibiting agonist and antagonist activities.
Figure 3: Building blocks for the synthesis of selective retinoid X receptor modulators.
Figure 4
Figure 5: RXR de-subordination by protein kinase A.
Figure 6: HDAC inhibitors as signalling pathway de-repressors.
Figure 7: Metabolic effects of rexinoids.

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Acknowledgements

L.A., A.R. de L. and H.G. thank all the members of their laboratories for their contributions to, and discussions of the work described. K.M.O. and M.D.L. are particularly indebted to M. Boehm and the rexinoid chemistry team who produced the compounds that were required for the work described. They also appreciate and acknowledge the contributions of P. Davies and the many individuals who participated in the described studies and discussions underlying them. Work in our laboratories is supported by grants from the European Union QLK3-CT2002-02029 and EPITRON LSHC-CT2005-518417 (L.A., A.R. de L., H.G.); the VINCI program and the Association pour la Recherche sur le Cancer (L.A., H.G.); the Ministero dell'Istruzione, Università e Ricerca (PRIN 2006052835_003), the Regione Campania L5 annualità 2005 (L.A.); SAF2004-07,131-FEDER (to A.R. de L.); the Ligue contre le Cancer (équipe labelisé), the Institut National de Cancer, the Association for International Cancer Research (AICR) and the European Union grants CRESCENDO LSHM-CT2005-018652 and X-TRA-NET LSHG-CT2005-018882 (H.G.).

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Correspondence to Hinrich Gronemeyer.

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M.D.L. and K.M.O. have been employees of Ligand Pharmaceuticals when the data reported on the metabolic effects of rexinoids were produced. L.A., A.R. de L. and H.G. declare that they have no competing financial interests.

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DATABASES

OMIM

Acute promyelocytic leukaemia

basal cell carcinoma

breast cancer

Kaposi's sarcoma

multiple myeloma

non-Hodgkin's lymophoma

non-small-cell lung cancer

neuroblastoma

obesity

ovarian cancer

prostate cancer

psoriasis

type 2 diabetes

FURTHER INFORMATION

Hinrich Gronemeyer's homepage

Clinical trials.gov database

Nuclear Receptor Signaling Atlas

Nuclear Receptor Database

Glossary

SNuRM

A selective nuclear receptor modulator; ligands that act in a cell-selective or tissue-selective manner, such as bone-selective oestrogens.

DNA methyltransferases

(DNMTs). These constitute a family of three enzyme isoforms that transfer methyl groups to cytosines of CpG islands often present in the promoter region of genes. Promoter methylation is presently considered a gene-silencing event. Moreover, aberrant areas of DNA hypermethylation, for example, of tumour-suppressor genes, and hypomethylation have been frequently found in cancers and are considered an important epigenetic event in tumorigenesis and/or cancer progression.

HDAC inhibitors

These are inhibitors of histone deacetylases (HDACs) and represent a growing class of chemically different compounds that can influence the acetylation status of histones. Moreover, acetylation and deacetylation of transcription factors (TFs) have also been reported and so HDAC inhibitors can regulate the activity of TFs, such as p53. There are three classes of HDACs, class 1 (HDACs 1, 2, 3, 8); class 2 (HDACs 4–7, 9–11); and the sirtuins (SIRT 1–7; class 3 HDACs). Mainly class 1 HDAC inhibitors have high potential as anticancer molecules and are currently enrolled in clinical trials for several cancers. The synthesis of enzyme-specific inhibitors may represent an important step for the use of HDAC inhibitors in cancer therapy.

TRAIL

Tumour necrosis factor-related apoptosis-inducing ligand (also known as APO2L or TNFSF10) and its death receptors — DR4 (also known as TRAILR1 or TNFRSF10A) and DR5 (also known as TRAILR2 or TNFRS10B) — are important regulators of the extrinsic pathway of apoptosis. Most interestingly, their expression (often silenced in tumours) can be induced by retinoids or rexinoid–protein kinase A crosstalk in leukaemias. An important concept is that the activity of TRAIL is tumour-selective and might be exploited in cancer therapy used as a recombinant protein and/or as a target gene of retinoid-based treatment and epigenetic modulations.

p21

Is a cyclin-dependent kinase (CDK) inhibitor; p21 is capable of binding to both cyclin–CDK and the proliferating cell nuclear antigen. By binding to CDKs, p21 inhibits the phosphorylation of the retinoblastoma protein by cyclin A–CDK2, cyclin E–CDK2, cyclin D1–CDK4 and cyclin D2–CDK4 complexes. p21 is induced by retinoic acid and by other differentiating and apoptosis-inducing agents such as histone deacetylase inhibitors.

Atypical retinoids

An increasing number of chemical compounds that share some (but not all) functions of retinoids. Examples are CD437 (6-[3-(1-adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid) and 4-HPR (N-[4-hydroxyphenyl] retinamide; also known as fenretinide). Often, atypical retinoids show activities, such as induction of cell death, which are believed not to be mediated by the corresponding retinoic acid receptors.

AKT

AKT is a serine/threonine kinase with Src homology (SH2) and Pleckstrin homology (PH) domains, activated by inositol (1,4,5) trisphosphate kinase downstream of insulin and other growth-factor receptors. AKT phosphorylates glycogen synthase kinase 3 and is involved in control of cell survival.

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Altucci, L., Leibowitz, M., Ogilvie, K. et al. RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6, 793–810 (2007). https://doi.org/10.1038/nrd2397

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