Retinoid pathway and cancer therapeutics

The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol-binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid x receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with an emphasis on the application of retinoids in cancer treatment and prevention.     

Recent developments of retinoids as therapeutic agents

Retinoids, a group of natural and synthetic retinol (vitamin A) analogues, play an important role in regulating pleiotropic biological events, including growth, differentiation and death of normal, premalignant and malignant cell types, which appears to account for their therapeutic or preventive effects in acne, psoriasis, photoageing, cancer and other diseases. Nuclear retinoic acid receptors and retinoid X receptors are thought to mediate the majority of retinoid biological effects. One effective strategy is to design and synthesise retinoids with receptor selectivity restricted to specific retinoic acid receptors or retinoid X receptor subtypes (α, β and γ) in order to develop novel retinoids with a more favourable therapeutic index and with reduced adverse effects and teratogenic risk. Indeed, retinoid medicinal chemistry has identified ligands that include highly specific antagonists for one of the three RAR subtypes and for retinoid X receptors. Since the retinoid X receptors also serve as heterodimer partners for several other nuclear receptors, including thyroid hormone receptors, vitamin D receptors, peroxisomal proliferator-activator receptors, Farnesoid X receptors and liver X receptors, retinoid X receptor-selective retinoids may have clinical applications for the prevention and treatment of diseases other than dermatological diseases and cancer, such as diabetes, obesity and atherosclerosis.     

Retinoid related molecules: new promises against lung and breast cancer

Retinoids have long interested cancer researchers due to their well-documented antiproliferative and differentiation inducing activities. However, natural compounds such as all-trans and 9-cis retinoic acid, as well as related synthetic derivatives, show only moderate anticancer activities, while at the same time inducing a broad range of undesirable activities. By taking advantage of the newly gained understanding in retinoid action and screening large numbers of novel molecules, new potent anticancer agents have been discovered that often lack typical retinoid side effects. Two of these novel types of molecules, referred to here as retinoid related molecules (RRMs), are described, one of which effectively kills non small cell lung cancer cells by apoptosis and is effective and well tolerated in vivo, while the other one belongs to a class of molecules selective for the nuclear receptor, RXR, which promises to be more effective and more tolerable than presently used compounds in anti-breast cancer adjuvant therapy. These novel molecules demonstrate the potential of novel RRMs that vastly outreaches classical retinoids.     

Selective retinoids and rexinoids in cancer therapy and chemoprevention

Natural and synthetic retinoids are effective inhibitors of tumor cell growth in vitro and in vivo. However, the toxicity of natural derivatives of vitamin A limits their therapeutic use. Recently, synthetic compounds selective for the different retinoid receptor isotypes have been generated that circumvent pan-retinoid toxicity. The tumor-suppressive activity of selective retinoid and/or rexinoid ligands has been established preclinically, and emerging clinical trials are supportive of the chemotherapeutic and chemopreventive potential of these compounds in multiple oncology indications, with reduced toxicity. Moreover, the combination of retinoids and/or rexinoids with chemotherapeutic agents for the synergistic modulation of specific pathways could also be of benefit in cancer therapy.     

Modulation of endothelial cell proliferation by retinoid x receptor agonists

One feature that contraindicates the wide therapeutic use of natural retinoids is their adverse effects during systemic use and the lack of receptor selectivity. In contrast, synthetic retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of selective retinoid receptors. We examined the inhibitory activities of natural and synthetic retinoids for their ability to reverse basic fibroblast growth factor-induced endothelial cell proliferation. Both the naturally occurring retinoids at nanomolar concentrations reversed basic fibroblast growth factor-induced endothelial cell proliferation. Among the synthetic retinoids tested, retinoic acid receptor/retinoid x receptor pan-agonist AGN 191659 [(E)-5-[2-(5,6,7, 8-tetrahydro-3, 5,5,8,8-pentamethyl-2-naphtyl) propen-1-yl]-2-thiophenecarboxylic acid] and retinoid x receptor pan-agonist AGN 191701 [(E)-2-[2-(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthyl) propen-1-yl]-4-thiophenecarboxylic acid] at nanomolar concentrations reversed the basic fibroblast growth factor-induced endothelial cell proliferation. Since none of the retinoic acid receptor agonists tested had any effect, the inhibitory effect of AGN 191659 could be attributed to its retinoid x receptor receptor activity. These results suggest that retinoid x receptor agonists may be more selective anti-angiogenic agents due to their ability to inhibit endothelial cell proliferation.     

A comparison of pentane-1,5-diol to other diols for use in dermatology

Retinoids have long interested cancer researchers due to their well-documented antiproliferative and differentiation inducing activities. However, natural compounds such as all-trans and 9-cis retinoic acid, as well as related synthetic derivatives, show only moderate anticancer activities, while at the same time inducing a broad range of undesirable activities. By taking advantage of the newly gained understanding in retinoid action and screening large numbers of novel molecules, new potent anticancer agents have been discovered that often lack typical retinoid side effects. Two of these novel types of molecules, referred to here as retinoid related molecules (RRMs), are described, one of which effectively kills non small cell lung cancer cells by apoptosis and is effective and well tolerated in vivo, while the other one belongs to a class of molecules selective for the nuclear receptor, RXR, which promises to be more effective and more tolerable than presently used compounds in anti-breast cancer adjuvant therapy. These novel molecules demonstrate the potential of novel RRMs that vastly outreaches classical retinoids.     

Novel synthetic retinoids and separation of the pleiotropic retinoidal activities

Retinoids, all-trans-retinoic acid (1a) and its analogs, act as specific modulators of cellular differentiation and proliferation, through binding to and activating specific nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Retinoids have chemotherapeutic roles in dermatology and oncology, but their usefulness is restricted by the high toxicity of retinoic acid and its hydrophobic analogs. We have developed various retinoidal benzoic acid derivatives, and named them retinobenzoic acids. Among them, aromatic amides such as Am80 (7) and Am580 (8) have superior pharmacological characteristics, including RAR subtype selectivity. Structural modification based on the ligand superfamily concept afforded several types of RAR antagonists, benzimidazole derivatives, BIPh (41) and BIBn (42), and dibenzodiazepine derivatives, LE135 (46) and LE540 (47). LE135 (46) is a unique antagonist with RARbeta-selectivity. During investigations on the structure-activity relationships of retinobenzoic acids, several retinoid synergists (RXRs agonists), such as HX600 (49), DA113 (55h) and TZ335 (57), have been found. These compounds are expected to modulate other nuclear receptors which form heterodimers with RXRs, besides retinoids. Further, we found some RXRs antagonists, HX531 (60) and HX603 (61), which inhibit the activation of both RXR homodimers and RXR RAR heterodimers. In this review, we describe our investigations on these structurally and biologically unique retinoids and retinoid-regulatory compounds.     

A new generation of retinoid drugs for the treatment of dermatological diseases

Dermatological diseases such as acne, psoriasis, and various skin cancers affect approximately 24 million people in the US (17 million acne, 6.4 million psoriasis and 0.7 million skin cancer). In many cases, particularly for acne and psoriasis, these diseases have exhibited favourable responses to single agent or adjuvant retinoid therapy. When administered as both chemotherapeutic and chemopreventive agents, they offer a viable alternative to classical cancer chemotherapy. Although retinoid treatment has shown considerable promise, certain side-effects have limited their utility for chronic administration. Accordingly, there is considerable interest in developing novel retinoids that exhibit improvements in the side-effect profile, particularly for diseases that require chronic administration. Retinoids are potent biological modulators that exert their effects through intracellular receptors (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) where they regulate cellular proliferation, differentiation and programmed cell death. Currently, using a combination of molecular biology and synthetic chemistry, efforts are underway to fully characterise the biological role of individual retinoid receptor subtypes. Using receptor-selective retinoids, recent discoveries have assisted in clarifying the mechanism and biological function of retinoids and their receptors. It now appears that the RARs are implicated in the regulation of cellular proliferation and differentiation, whereas the RXRs function as modulators of programmed cell death or apoptosis. This suggests that diseases that are associated with abnormal proliferation and/or differentiation may be treatable with RAR active compounds. In fact, the data are supported by successful treatment of psoriasis, epithelial cancer and leukaemia with retinoids that preferentially activate the RARs. In contrast, retinoids that preferentially activate RXRs may be desirable for treatment of diseases for which enhancement of apoptosis is required. For example, they are potentially useful for treatment of cutaneous T-cell lymphoma and as chemopreventive agents [1]. The mechanisms of action of these RXR mediated effects are under investigation. Finally, certain receptor subtypes are implicated in retinoid side-effects. For example, it has become increasingly evident that side-effects such as triglyceridaemia [2] and teratogenesis [3,4] can be correlated to activation of the RARs and not the RXR. These findings offer opportunities for developing a new generation of retinoids which exhibit improved therapeutic indices. Recently, novel treatment strategies have evolved including the application of receptor-selective synthetic retinoids, combination therapies with other hormones or chemotherapeutic agents, and novel formulations. This has resulted in a new generation of retinoids and retinoid treatments which are in clinical development and which exhibit improvements in the therapeutic index.     

具有抗肿瘤作用的维甲酸类化合物的研究进展

综述具有抗肿瘤活性的维甲酸类化合物的研究现状，并展望其今后的研究动向。维甲酸类化合物通过激活其核受体蛋白来调控核基因的表达，产生抗肿瘤作用，其中一些有望成为临床抗肿瘤药物。     

Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes

Obesity and type II diabetes are closely related metabolic diseases with an increasing incidence worldwide. No clear-cut pharmacological treatment for these complex metabolic disturbances is available despite current efforts. New directions and perspectives for the pharmacological or nutritional treatment of these diseases should be defined. In recent years, a growing body of evidence shows that retinoids and retinoic acid receptors are involved in the control of biological aspects (e.g. adiposity and energy expenditure mechanisms), which offers great potential for research on the treatment of obesity and type II diabetes. All-trans retinoic acid is known to inhibit adipocyte differentiation, whereas, molecules activating the retinoid X-receptor (rexinoids) promote the differentiation of adipocytes. Treatment with rexinoids ameliorates glycemic control in rodent models of type II diabetes and obesity, although other findings indicate similar positive effects by inhibiting the receptor. Moreover, natural products of dietary origin, such as phytanic acid can activate RXR and thus, trigger adipose cell differentiation. Finally, the activation of retinoic acid receptors or retinoid X receptors has been reported to induce the gene expression of uncoupling proteins, which are mitochondrial proteins involved in the regulation of energy expenditure and fatty acid metabolism. Further research is required to exploit the capacities of the retinoid-dependent pathways of regulation of adiposity, insulin sensitivity and energy expenditure for drug development in metabolic disturbances.     

Central effects of clozapine in regulating micturition in anesthetized rats

Background

Retinoids are very potent inducers of cellular differentiation and apoptosis, and are efficient anti-tumoral agents. Synthetic retinoids are designed to restrict their toxicity and side effects, mostly by increasing their selectivity toward each isotype of retinoic acids receptors (RARα,β, γ and RXRα, β, γ). We however previously showed that retinoids displayed very different abilities to activate retinoid-inducible reporter genes, and that these differential properties were correlated to the ability of a given ligand to promote SRC-1 recruitment by DNA-bound RXR:RAR heterodimers. This suggested that gene-selective modulation could be achieved by structurally distinct retinoids.

Results

Using the differential display mRNA technique, we identified several genes on the basis of their differential induction by natural or synthetic retinoids in human cervix adenocarcinoma cells. Furthermore, this differential ability to regulate promoter activities was also observed in murine P19 cells for the RARβ2 and CRABPII gene, showing conclusively that retinoid structure has a dramatic impact on the regulation of endogenous genes.

Conclusions

Our findings therefore show that some degree of selective induction or repression of gene expression may be achieved when using appropriately designed ligands for retinoic acid receptors, extending the concept of selective modulators from estrogen and peroxisome proliferator activated receptors to the class of retinoid receptors.     

Selective retinoic acid receptor ligands for rheumatoid arthritis

Retinoids, modulators of retinoic acid receptors (RARs), have been studied for over 20 years as potential therapeutic agents for rheumatoid arthritis (RA). Early successes at the in vitro and in vivo levels were overshadowed by disappointing clinical trials that yielded poor efficacy and unacceptable side effects. A greater understanding of retinoid biology has led to the development of many synthetic retinoids that selectively modulate the RAR isotypes. RAR selective retinoids have a high potential for improved pharmacology with reduced toxicity, thereby renewing interest for the use of retinoids in RA.     

Retinoids for the treatment of psoriasis: outlook for the future

Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. Firstly, the binding of retinoids to nuclear retinoic acid receptors (RARs) does not match their therapeutic efficacy. Secondly, formation of retinoic acid is probably increased in the psoriatic lesions. Answering these questions should result in: (i) the better use of acitretin, an oral synthetic retinoid, and tazarotene, the first compound for topical use; (ii) the development of new retinoids with specific pharmacological profile such as subtype-selective retinoids including molecules with an 'antiretinoid' activity and dissociating antiproliferative retinoids; and (iii) the better characterization of non-genomic effects of retinoids.     

International Union of Pharmacology. LX. Retinoic acid receptors

Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARalpha, RARbeta, and RARgamma), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-trans-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.