Retinoic acid signaling pathways in development and diseases

doi:10.1016/j.bmc.2013.11.025

Bioorganic & Medicinal Chemistry

Volume 22, Issue 2, 15 January 2014, Pages 673-683

https://doi.org/10.1016/j.bmc.2013.11.025 Get rights and content

Abstract

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon–oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.

Graphical abstract

This graphical abstract represents the chemical structures of retinoic acid and several synthetic derivative retinoids, the use of these chemicals for probing mechanisms of developmental and cell biology, as well as their use as therapeutic agents for treating cancer and neurological disorder disease.

Introduction

Vitamin A or retinol is a fat-soluble compound derived from [beta]-carotene found in plants and retinyl esters from animal sources. It is stored in the liver and adipose tissue as retinyl esters and circulates in the blood in a protein complex containing retinol binding protein and transthyretin. Retinoic acid, the main derivative of vitamin A, binds to nuclear receptors, retinoic acid receptor (RAR) and retinoic X receptor (RXR) to regulation gene transcription. RA plays an important role in tissue development and differentiation. This review focuses on the role of RA in development and diseases, and the development of synthetic RA compounds for therapy and molecular imaging.

Section snippets

Synthesis, chemistry and analysis of RA

Retinoids comprise a group of compounds related to vitamin A, including its natural and synthetic analogues, which contain four isoprenoid units joined in a head-to-tail fashion. The basic structure of a retinoid consists of three parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that serves as a linker unit, and a polar carbon–oxygen functional group, typically carboxylic acid as shown in Figure 1.

Retinoids are unstable due to the

Retinoid and carotenoid metabolism

Carotenoids or other retinoids are biochemically converted to retinoic acid (RA), which is essential for modulating a wide range of biological processes including development, differentiation, proliferation, and apoptosis. The bioconversion takes place successively (Fig. 3), first in the intestine, then the liver, and finally in target cells with the support of various binding proteins including cellular retinol-binding proteins (CRBPs), retinol-binding proteins (RBPs), and cellular retinoic

Genomic action of retinoids

Retinoids regulate various biological activities by binding RARs and RXRs. Ligand binding to the receptor causes conformational changes that modulate receptor complex function. In addition, these receptor complexes have a range of additional co-activators and co-repressors that modulate receptor activity. The composition of receptor complex is complicated by the presence of distinct subtypes and isoforms. Both RAR and RXR have three subtypes α, β, and γ, each with different isoforms. RARα and

RA signaling in normal development

The requirement for retinoids during embryogenesis has been long appreciated, since vitamin A is an essential dietary requirement. Yet for understanding mechanism, it is perplexing that loss of signaling or hyper-activation of the pathway can generate similar phenotypes. For example, excess RA causes many of the same embryonic developmental defects seen with vitamin A deficiency (VAD), which is why vitamin A intake levels should be monitored carefully during pregnancy. Because RA is

Retinoids in diseases

Though RA and it is analogs are essential for normal regulation of a wide range of biological processes, while deregulated retinoid signaling can contribute to serious diseases. In this section, we will briefly describe, how aberrant signaling of RA causes diseases, and how synthetic retinoids are used to treat some diseases.

Drug discovery and use of retinoids for treatment of diseases

As described above, several natural and synthetic retinoids have moved to clinical trials for various types of cancer, while several other classes of synthetic retinoids continue to be investigated at the pre-clinical level for anti-cancer activities. A major strategy to develop various synthetic retinoid derivatives with the potential to impart different biological activities is to systematically modify the hydrophobic, linker, or hydrophilic moieties of RA.

Recently, a series of acitretin

Retinoids in molecular imaging

Molecular imaging plays a very important role in the field of drug discovery. It provides a useful tool to track molecules and identify the molecular targets. Fortunately, an imageable RA derivative has been reported. The imageable compound 40 (Fig. 21) was developed by the conjugation of IRdye800cw and N-(aminohexyl0retinoicamide) [RA-NH(CH2)₆NH₂]. This near-infrared (NIR)-labeled agent was used for both in vitro and in vivo imaging studies. It can be used to detect multiple human cancer

Retinoids in stem cell biology and regenerative medicine

Retinoids regulates the stem cell differentiation via transcription activation. Retinoids are able to activate transcription by binding to the nuclear receptors RARα, RARβ, and RARγ. These RARs can form heterodimer with one of the RXRs and can bind with the DNA. This binding facilitates the activation of transcription of RA primary response genes, which are important for stem cell differentiation.¹¹⁴ Stem cells are unspecialized cells that have the ability to self-reproduce and differentiate

Conclusions

Retinoids comprise a group of natural and synthetic molecules, which regulate a variety of essential biological processes during normal development, help maintain homeostasis, and also mediate protection from diseases such as cancer and age-related disorders of the CNS. Genomic functions of the retinoids are mediated via their nuclear DNA-binding receptors, RARs and RXRs, which regulate gene transcription through recruitment of corepressors and coactivators. Retinoids also have notable

Acknowledgments

B.C.D. is thankful to University of Kansas Medical Center for startup funding. B.C.D. is supported by Grants from the NIH (AA020630 and AI093220). D.W.P. is supported by Grant from NIH (DK081579). T.E. is supported by Grants from the NIH (HL56182, HL111400) and NYSTEM (C028100).

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¹: Both authors contributed equally to the paper.

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ReviewRetinoic acid signaling pathways in development and diseases

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis, chemistry and analysis of RA

Retinoid and carotenoid metabolism

Genomic action of retinoids

RA signaling in normal development

Retinoids in diseases

Drug discovery and use of retinoids for treatment of diseases

Retinoids in molecular imaging

Retinoids in stem cell biology and regenerative medicine

Conclusions

Acknowledgments

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Clin. Immunol. Immunopathol.

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Biochem. Biophys. Res. Commun.

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Blood

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Cell

Nutrition

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Exp. Cell Res.

Differentiation

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Review
Retinoic acid signaling pathways in development and diseases