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PubMed2003

Retinoid receptors and vitamin A deficiency: differential patterns of transcription during early avian development and the rapid induction of RARs by retinoic acid.

The functional links of specific retinoid receptors to early developmental events in the avian embryo are not known. Before such studies are undertaken, knowledge is required of the spatiotemporal expression patterns of the receptor genes and their regulation by endogenous retinoic acid levels during the early stages of development. Here, we report the expression patterns of mRNAs for RARalpha, RARalpha2, RARbeta2, RARgamma, RARgamma2, RXRalpha, and RARgamma from neurulation to HH10 in the normal and vitamin A-deficient (VAD) quail embryo. The transcripts for all retinoid receptors are detectable at HH5, except for RXRgamma, which is detected at the beginning of HH6. At the 4/5 somite stage of HH8, when retinoid signaling is initiated in the avian embryo, mRNAs of all receptors are present, with very strong and ubiquitous expression patterns for RARalpha, RARalpha2, RARgamma, RARgamma2, and RXRalpha, a persistent expression of RARgamma in the neural tissues, a strong expression of RARbeta2 in lateral plate mesoderm and somites, and an anterior expression of RXRgamma. All retinoid receptors are expressed in the heart primordia. In the VAD quail embryo, the general pattern of retinoid receptor transcript localization is similar to that of the normal, except that the expression of RARalpha2 and RARbeta2 is severely diminished. Administration of retinol or retinoic acid to VAD embryos at or before the 4/5 somite stage rescues the expression of RARalpha2 and RARbeta2 within approximately 45 min and restores normal development. RARbeta2 expression requires the expression of RARalpha2. After neurulation, the expression of all retinoid receptors in the VAD quail embryo becomes independent of vitamin A status and is similar to that of the normal. The mRNA levels and sites of expression of the key enzyme for retinoic acid biosynthesis, Raldh-2, are not affected by vitamin A status; the expression pattern is restricted and does not correspond to that of retinoid receptors at all sites. The general patterns and intensity of retinoid receptor gene expression during early quail development are comparable to those of the mammalian and thus validate the application of results from retinoid-regulated avian development studies to those of the mammalian.

Aldehyde Oxidoreductases↗

PubMed1998

Future trends: a new generation of retinoids.

The existence of several different types of retinoid receptors, response elements, and cofactors means that retinoid physiology is mediated by multiple discrete pathways and is highly complex. As a result, non-selective retinoids have a multitude of physiologic effects and are usually associated with toxicity problems that limit their therapeutic usefulness. In contrast, because receptor-selective retinoids have a more focused and targeted action, they are likely to have a better therapeutic index. Tazarotene is the first of a new generation of receptor-selective retinoids. Its actions are targeted on 2 retinoic acid receptors (RARs), RAR-beta and RAR-gamma. Current retinoid research is leading to the development not only of many more novel receptor-selective retinoids but also of novel types of function-selective retinoids such as RAR inverse agonists and RAR antagonists. These retinoids are expected to be of clinical benefit not only in dermatology but also in oncology, diabetes, and diseases associated with the human papilloma virus.

Administration, Cutaneous↗

PubMed2003

Topical and systemic retinoid therapy for cutaneous T-cell lymphoma.

Because curative therapies for CTCL are not yet available, short of TSEB in patients who have early-stage disease and allogeneic bone marrow transplantation in patients who have more advanced disease, the goal of current therapies is to prevent progression of MF and to preserve quality of life. The overall conclusion drawn from the studies reported in the literature, is that retinoids as monotherapy, or in combination with other nonaggressive treatment modalities, represent a low-risk treatment alternative that is especially suitable for controlling early stages of MF and other CTCL. A combination of therapies may be more effective in controlling CTCL as shown with IFN-alpha plus retinoids, and, recently, IFN-alpha with bexarotene and other modalities. For example, isotretinoin, followed by TSEB (for stage I to II disease) or preceded by chemotherapy (for stage II and IV disease) and bexarotene plus PUVA or photopheresis plus IFN, gave overall response rates of 82% and 69% in patients who had MF and SS, respectively. Retinoids as monotherapy may induce complete remissions, but usually these responses are of short duration and relapses are common. Clinical response is not identical to histologic clearance. Even in cases with clinically complete clearance of skin lesions, lymphoid infiltrates persisted, which are most likely the source of recurrences. The new generation of retinoids, the RXR selective agonists like bexarotene, represent a promising approach for refractory or persistent MF that is unresponsive to first-line therapies. Individual differences in response to retinoids may be due to different expression of retinoid receptors, functional polymorphisms in metabolizing retinoids, or resistance to some retinoids. In the future, pharmacogenomic studies are needed to clarify the mechanisms that underlie the differing response rates of patients who have CTCL to retinoids. In addition, new agonists of RAR and RXR, either selective or pan agonists, will become available and will enlarge the spectrum of vitamin A analogs that have antitumoral properties.

Adjuvants, Immunologic↗

PubMedDate not supplied

Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer.

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer.

Anticarcinogenic Agents↗

PubMed2001

Heterocycle-containing retinoids. Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptosis-resistant cells.

In a search for retinoic acid (RA) receptor ligands endowed with potent apoptotic activity, a series of novel arotinoids were prepared. Because the stereochemistry of the C9-alkenyl portion of natural 9-cis-RA and the olefinic moiety of the previously synthesized isoxazole retinoid 4 seems to have particular importance for their apoptotic activity, novel retinoid analogues with a restricted or, vice versa, a larger flexibility in this region were designed and prepared. The new compounds were evaluated in vitro for their ability to activate natural retinoid receptors and for their differentiation-inducing activity. Cytotoxic and apoptotic activities were, in addition, evaluated. In general, these analogues showed low cytotoxicity, with the restricted structures being slightly more active than the more flexible ones. As an exception, however, the isoxazole retinoid 15b proved to be particularly able to induce apoptosis at concentrations <5 microM, showing a higher activity than the classical retinoids such as all-trans-RA, 13-cis-RA, and 9-cis-RA and the previously described synthetic retinoid 4. 15b also exhibited a good affinity for the retinoid receptors. Interestingly, another important property of 15b was its ability to induce apoptosis in the HL60R multidrug-resistant (MDR) cell line, at the same concentration as is effective in HL60. Therefore, 15b represents a new retinoid possessing high apoptotic activity in an MDR cell line. The ability of 15b to act on K562 and HL60R cells suggests that this compound may have important implications in the treatment of different leukemias, and its structure could offer an interesting model for the design of new compounds endowed with apoptotic activity on MDR- and retinoid-resistant malignancies.

Antineoplastic Agents↗

PubMed1998

Growth inhibition of human in vitro and mouse in vitro and in vivo mammary tumor models by retinoids in comparison with tamoxifen and the RU-486 anti-progestagen.

Retinoids constitute a very promising class of agents for the chemoprevention or treatment of breast cancer. These retinoids exert their biological activity through two distinct classes of retinoic acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma) and their numerous isoforms which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. With respect to these numerous receptor sub-types, the retinoid-induced effects at the biological level include marked modifications with respect to both cell proliferation and cell death (apoptosis), and also in the induction of differentiation processes. The present study aims to characterize the effect which four retinoids (TTNPB, 9-cis-RA, LGD 1069, 4-HPR) with distinct RAR/RXR binding properties induced on various in vitro and in vivo mouse and human breast cancer models. The experiments with the retinoids were carried out in comparison with the anti-estrogen tamoxifen and the anti-progestagen RU-486 compounds. The results show that the 6 compounds under study were markedly more efficient in terms of growth inhibition in the human T-47D cell line when maintained under anchorage-independent culture conditions than when maintained under anchorage-dependent ones. While RU-486 exhibited a weak statistically significant (p < 0.05) influence on the growth of the T-47D stem cells, tamoxifen had a marked inhibitory influence on the growth of these cells. Of the four retinoids, 4-HPR was the least effective since the lowest doses tested (1 and 0.1 nM) exhibited no statistically (p > 0.05) significant influence on the growth of the stem cells. The most efficient retinoid was TTNPB. It was only at the highest dose (10 microM) that tamoxifen and RU-486 showed a weak inhibitory influence on the growth of the T-47D non-stem cells while all 4 retinoids exerted a significant inhibitory influence on the growth of these non-stem cells, with 4-HPR being the most efficient (P < 0.001) at the highest dose, but ineffective (P > 0.05) at the lowest. Tamoxifen and TTNPB were tested in vivo on hormone-sensitive (HS) and hormone-insensitive (HI) strains of the MXT murine mammary carcinoma. While TTNPB appeared to be equally efficient in terms of growth inhibition in both MXT-HS and MXT-HI models, tamoxifen had only a marginal inhibitory influence on the growth of the MXT-HI strain but did inhibit growth in the case of the MXT-HS one. TTNPB was markedly more efficient than tamoxifen in terms of both inhibiting the cell proliferation level (measured by means of computer-assisted microscopy applied to Feulgen-stained nuclei, a method which enables the percentage of cells in the S phase of the cell cycle to be determined) and triggering cell death (measured by means of the determination of the transglutaminase activity) in both the MXT-HI and MXT-HS models. The very significant TTNPB-induced inhibition of the macroscopic MXT-HS growth rate relates to the triggering of cell death (apoptosis) rather than to an inhibition of cell proliferation. All these results clearly indicate that retinoids are very efficient agents against breast cancer, at least as efficient as tamoxifen.

Alitretinoin↗

PubMed1998

Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells.

During carcinogenesis, pancreatic acinar cells can dedifferentiate into ductal adenocarcinoma of the pancreas. DSL-6A/C1 cells represent an in vitro model of this carcinogenic sequence. This study was designed to examine the effects of retinoids on cell growth in DSL-6A/C1 cells and to characterize further the molecular mechanisms underlying the antiproliferative actions of retinoids. Treatment of DSL-6A/C1 cells with retinoids results in a time- and dose-dependent inhibition of cell growth, paralleled by a retinoid-mediated transactivation of a pTK::betaRAREx2-luciferase reporter construct transiently transfected into DSL-6A/C1 cells. Retinoid receptor expression was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) using subtype-specific primers and demonstrated expression of retinoic acid receptor alpha (RAR-alpha), RAR-beta and retinoid X receptor alpha (RXR-alpha). Using a panel of receptor subtype-specific agonists, the RAR-alpha specific agonist Ro 40-6055 was the most potent retinoid in terms of growth inhibition. Furthermore, all-trans-retinoic acid-mediated growth inhibition and transactivation was completely blocked by the RAR-alpha-specific antagonist Ro 41-5253. In summary, the RAR-alpha subtype predominantly mediates the antiproliferative effects of retinoids in DSL-6A/C1 cells. Furthermore, this cell system provides a feasible tool to study the molecular mechanisms underlying the growth inhibitory effects of retinoids in ductal pancreatic carcinoma cells derived from a primary acinar cell phenotype.

Animals↗

PubMed1999

Retinoids: present role and future potential.

Vitamin A and its biologically active derivatives, retinal and retinoic acid (RA), together with a large repertoire of synthetic analogues are collectively referred to as retinoids. Naturally occurring retinoids regulate the growth and differentiation of a wide variety of cell types and play a crucial role in the physiology of vision and as morphogenic agents during embryonic development. Retinoids and their analogues have been evaluated as chemoprevention agents, and also in the management of acute promyelocytic leukaemia. Retinoids exert most of their effects by binding to specific receptors and modulating gene expression. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors. In this article we review the use of retinoids in chemoprevention strategies, discuss the cellular consequences of activated retinoid receptors, and speculate on how our increasing understanding of retinoid-induced signalling pathways may contribute to future therapeutic strategies in the management of malignant disease.

Animals↗

PubMed1996

Retinoids in cancer chemoprevention.

Naturally occurring and synthetic vitamin A metabolites and analogs (retinoids) inhibit tumor development in a variety of cellular, animal, and patient studies. They suppress transformation of cells in vitro and inhibit carcinogenesis in various organs in animal models. In a mouse skin carcinogenesis model, topical retinoids exhibit suppressive effects on tumor promotion, but have no effect on tumor initiation. In other models, retinoids administered in the diet suppress tumor development even in an adjuvant setting after excision of the first tumor. Retinoids suppress carcinogenesis in individuals with premalignant lesions and a high risk to develop cancer of the aerodigestive tract. Likewise, retinoids prevent the development of second primary cancers in head/neck and lung cancer patients who had been treated for the first primary. The mechanisms underlying the anticarcinogenic activity of retinoids appear to be associated with the ability of retinoids to modulate the growth, differentiation, and apoptosis of normal, premalignant, and malignant cells in vitro and in vivo. Most of these effects are mediated by nuclear retinoid receptors, but other mechanisms may also be involved. These studies indicate that retinoids are potentially useful agent for cancer chemoprevention.

Animals↗

PubMed1993

Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol.

Studies have been conducted to investigate the structure-function relationships of retinoids in their in vitro interaction with plasma retinol-binding protein (RBP) and in their influence on plasma retinol concentration. Two classes of retinoids, one bearing modifications in the area of the retinol hydroxyl end group (fenretinide, N-(ethyl) retinamide, all-trans, and 13-cis retinoic acid) and the other one also bearing modifications in the area of the cyclohexene ring (etretinate, acitretin, and arotinoid Ro 13-7410), were investigated. Whereas substantial modifications of the retinol hydroxyl group do not prevent the binding to RBP, an intact trimethylcyclohexenyl group seems to be crucial for binding. Both classes of retinoids, administered orally at equimolar doses, reduce plasma retinol concentration in rats but with different kinetics. A marked lowering of plasma retinol occurs early (within 5 h) after administration of retinoids that interact with RBP in vitro, whereas it occurs at later times (24 h) after retinoids that do not interact with RBP. The concentrations of both classes of retinoids found in plasma do not account for the temporal difference in this effect. The early reduction of plasma retinol might be the consequence of in vivo specific binding of retinoids to RBP, as suggested by the in vitro results. The late reduction observed for retinoids lacking in vitro affinity for RBP is due to other mechanisms or to metabolism to retinoids binding to RBP.

Animals↗

PubMed1988

Inhibition of pancreatic and liver carcinogenesis in rats by retinoid- and selenium-supplemented diets.

Chemoprevention by a synthetic retinoid, selenium, and these agents in combination during the postinitiation stages of carcinogenesis induced in rats by azaserine was evaluated. Male Lewis rats were given three weekly injections of 30 mg/kg azaserine while being fed a purified diet. One week after completion of carcinogen treatment, groups of rats were switched to the purified diet supplemented with either a retinoid, N-(2-hydroxyethyl)retinamide, at a level of 0.5 or 1 mmol/kg diet, or with 5 ppm sodium selenite, or with a combination of retinoid and selenium. One year after the diet change, the incidence of pancreatic and other neoplasms was determined by autopsy and histologic study. The incidence of pancreatic carcinoma (including carcinoma-in-situ, CIS) among nonretinoid-treated controls was 68%. Since the dietary supplements were fed after completion of exposure to the carcinogen, the effects on both pancreatic and liver carcinogenesis were exerted during the postinitiation phase of carcinogenesis. As in previous studies, the retinoid inhibited the progression of pancreatic carcinogenesis in a dose-related fashion. Selenium alone had no effect. However, the combination of retinoid plus selenium was more effective than retinoid alone, although the increase in inhibition was not large. The retinoid was also found to inhibit liver carcinogenesis induced by azaserine. Selenium, either alone or in combination with retinoid, was ineffective. Finally, testicular atrophy, noted as a toxic effect of retinoids in other studies, was not observed in this work.

Animals↗

PubMed1999

Structures of cellular retinoic acid binding proteins I and II in complex with synthetic retinoids.

Retinoids play important roles in diverse cellular processes including growth, cell differentiation and vision. Many natural and synthetic retinoids are used as drugs in dermatology and oncology. A large amount of data has been accumulated on the cellular activity of different synthetic retinoids. They are stabilized and transported inside the cell cytoplasm by binding and transport proteins, such as cellular retinol-binding proteins and cellular retinoic acid binding proteins (CRABPs). The structures of human CRABP II in complex with two different synthetic retinoids, Ro13-6307 and Ro12--7310 (at 2.1 and 2.0 A resolution, respectively) and of bovine CRABP I in complex with a retinobenzoic acid, Am80 (at 2.8 A resolution) are described. The binding affinities of human CRABP I and II for the retinoids studied here have been determined. All these compounds have comparable binding affinities (nanomolar range) for both CRABPs. Apart from the particular interactions of the carboxylate group of the retinoids with specific protein groups, each structure reveals characteristic interactions. Studying the atomic details of the interaction of retinoids with retinoid-binding proteins facilitates the understanding of the kinetics of retinoid trafficking inside the cytoplasm.

Animals↗

PubMed2003

Retinoids: fascinating up-and-coming scenario.

Retinoids have been in sharp focus ever since their introduction 30 years ago. They include any drug (s) that bind to retinoid receptors and elicit a biological response. Enormous information on the subject seems to embroil the recent literature. Practically it is impossible to clearly comprehend the undercurrents. The meticulously dispensing text envisages surmounting the perspective reader's predicaments. Accordingly, retinoids and their related facets namely retinoid receptors, classification, mode of action, and the pharmacological diversity have been precisely defined. Commonly used systemic retinoids too have been given a substantial fresh look along with their monitoring. Overall, adverse effects and relative and absolute contraindications have been scrupulously incorporated. Human immuno deficiency virus (HIV) and isoretinoid for acne, in particular, have been highlighted. Micronized isotretinoin formulations have also been taken care so also commonly used topical retinoids. Tretinoin and their newer formulation have also been accounted for along with tretinoin polymer cream. Adapalene, a new chemical entity possessing a unique physico-chemical activity similar to that of tretinoin has also been dealt with. Newer retinoids are likely to be a subject of intrigue. A focus on future potentials of retinoids is its special ingredient. The inclusion of details of rexinoid the most recent introduction in their purview is likely to invoke interest to further consolidate its reckoning in future. All in all the text of the paper should provide an insight into the current rumbling around retinoids.

Acne Vulgaris↗

PubMed2006

Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years' experience on 23 patients.

BACKGROUND: Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children. OBJECTIVES: The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago. METHODS: Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes. RESULTS: Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate. CONCLUSIONS: This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids.

Acitretin↗

PubMed1988

Nonsurgical treatments for skin cancer: retinoids and alpha-interferon.

Retinoids, the natural and synthetic analogs of vitamin A, and alpha-interferon have been used effectively in the treatment of certain cutaneous premalignancies and malignancies. Retinoids have shown impressive activity against premalignant disorders of the skin (actinic keratoses, keratoacanthoma, epidermodysplasia verruciformis) and of other epithelial sites (oral leukoplakia, cervical dysplasia). In established basal cell skin cancers, topical retinoid treatment has produced a complete response rate of 33%, and systemic retinoids have produced an objective response rate of 51%. In advanced squamous cell skin cancers, systemic retinoids have produced a response rate of over 70%. Intralesional alpha-interferon has produced impressive responses and systemic alpha-interferon has produced a 50% objective response rate in basal and squamous cell carcinoma. Retinoid therapy and alpha-interferon have produced modest overall results in melanoma, although striking individual responses have been reported. In cutaneous T-cell lymphoma, which is notably refractory to chemotherapy, retinoids and alpha-interferon have produced responses in 60%+ and 70%+ of cases, respectively. Retinoids and alpha-interferon, either alone or in combination, offer exciting prospects for primary and neoadjuvant therapy for advanced malignancy. Retinoids also show promise as relatively nontoxic preventive and adjuvant therapy. Researchers should focus on integrating these drugs with other biological response modifiers, differentiation agents, and cytotoxic drugs for treating advanced malignancy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Spectral properties of topical retinoids prevent DNA damage and apoptosis after acute UV-B exposure in hairless mice.

We showed in a recent study that topical retinyl palmitate prevented UV-B-induced DNA damage and erythema in humans. Given that retinyl palmitate is a precursor of retinoic acid, the biological form of vitamin A that acts through nuclear receptors, we wondered whether these protective effects toward UV-B exposure were either receptor dependent or linked to other properties of the retinoid molecule such as its spectral properties. We determined the epidermal retinoid profile induced by topical retinoic acid in hairless mice and analyzed its effect on markers of DNA photodamage (thymine dimers) and apoptosis following acute UV-B exposure; we compared these effects to those induced by other natural topical retinoids (retinaldehyde, retinol and retinyl palmitate) which do not directly activate the retinoid receptors. We then analyzed the direct action of these retinoids on UV-B-induced DNA damage and apoptosis in cultured A431 keratinocytes. Topical retinoic acid significantly decreased (approximately 50%) the number of apoptotic cells, as well as the formation of thymine dimers in the epidermis of mice exposed to acute UV-B. Interestingly, the other topical retinoids decreased apoptosis and DNA damage in a similar way. On the other hand, neither retinoic acid nor the other retinoids interfered with the apoptotic process in A431 keratinocytes exposed to UV-B, whereas DNA photodamage was slightly decreased. We conclude that the decrease of apoptotic cells in hairless mouse epidermis following topical retinoids and UV-B irradiation reflects a protection of the primary targets of UV-B (DNA) by a mechanism independent of the activation of retinoid nuclear receptors, rather than a direct inhibition of apoptosis.

Animals↗

PubMed1997

Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation.

Vitamin A and its derivatives, the retinoids, are essential regulators of many important biological functions, including cell growth and differentiation, development, homeostasis, and carcinogenesis. Natural retinoids such as all-trans retinoic acid can induce cell differentiation and inhibit growth of certain cancer cells. We recently identified a novel class of synthetic retinoids with strong anti-cancer cell activities in vitro and in vivo which can induce apoptosis in several cancer cell lines. Using an electrophoretic mobility shift assay, we analyzed the DNA binding activity of several transcription factors in T cells treated with apoptotic retinoids. We found that the DNA binding activity of the general transcription factor Sp1 is lost in retinoid-treated T cells undergoing apoptosis. A truncated Sp1 protein is detected by immunoblot analysis, and cytosolic protein extracts prepared from apoptotic cells contain a protease activity which specifically cleaves purified Sp1 in vitro. This proteolysis of Sp1 can be inhibited by N-ethylmaleimide and iodoacetamide, indicating that a cysteine protease mediates cleavage of Sp1. Furthermore, inhibition of Sp1 cleavage by ZVAD-fmk and ZDEVD-fmk suggests that caspases are directly involved in this event. In fact, caspases 2 and 3 are activated in T cells after treatment with apoptotic retinoids. The peptide inhibitors also blocked retinoid-induced apoptosis, as well as processing of caspases and proteolysis of Sp1 and poly(ADP-ribose) polymerase in intact cells. Degradation of Sp1 occurs early during apoptosis and is therefore likely to have profound effects on the basal transcription status of the cell. Interestingly, retinoid-induced apoptosis does not require de novo mRNA and protein synthesis, suggesting that a novel mechanism of retinoid signaling is involved, triggering cell death in a transcriptional activation-independent, caspase-dependent manner.

Apoptosis↗

PubMed2002

Effect of natural and synthetic retinoids on the proliferation and differentiation of three canine melanoma cell lines.

The effect of two natural retinoids and synthetic retinoids with or without retinoid synergists on the proliferation and differentiation of 3 melanoma cell lines were investigated in vitro. No retinoids showed significant growth inhibitory effect on these cell lines when used alone, however, cell differentiation and significant growth inhibition were observed when treated with a combination of retinoids and a retinoid synergist. This study may suggest that, though the cells showed low susceptibilities when retinoids were treated alone, the combination of retinoids and a retinoid synergist may be effective to control the growth of canine melanoma cell lines.

Animals↗