Retinoid Molecules Research Articles

The rational of a fixed combination of benzoyl peroxide and niacinamide in the treatment of acne vulgaris: A narrative review

Acne vulgaris (AV) in a common skin disease affecting mainly adolescents but could be present also in adult subjects. AV is characterized by the presence of non-inflammatory (comedons) and inflammatory (papules, pustules, cysts, and nodules) lesions affecting sebaceous glands rich regions like the face, back, shoulder and thorax. A central pathogenetic role of AV lesions seems played by Cutibacterium acnes, especially some phylotypes (i.e. C. acne IA1) able to induce an inflammatory response at the level of sebaceous glands. Other important pathogenetic factors of AV are the adrogen-driven increase of sebum production and the process of hyperkeratinisation of the infundibulum. The first line treatment of AV is in general done using monotherapy with antibacterial agents like benzoyl peroxide (BPO) and hydrogen peroxide or topical retinoid molecules. These two classes of drugs could interfere with C. acnes growth (BPO) and with keratinocytes proliferation (retinoid). Fixed combination of BPO and retinoid molecules are commonly used in mild to moderate forms of AV. However, both BPO and retinoids could be nor well tolerated especially during the first weeks of treatment causing skin irritation erythema and and dryness. Both BPO and topical retinoids could interfere with the skin barrier function. During BPO treatment the Trans epidermal water loss (TEWL) a marker of skin barrier function, increase significantly supporting the fact that BPO alters this function. Niacinamide is a potent anti-inflammatory molecule able to preserve the skin barrier function. Niacinamide has shown to be effective in AV with inflammatory lesions. There is a strong rationale for the development of a topical product formed by fixed combination of BPO and niacinamide for the first-line treatment of mild to moderate AV but also in the treatment of papulopustular rosacea. In this narrative review we discuss the rational of the combination and the first clinical data of this product as first line AV and rosacea treatment strategy.

Vitamin A: It's role in cosmeceuticals for antiaging

AbstractTopical retinoids are among the most well‐studied and widely used cosmeceutical ingredients. Topical retinoids have skin rejuvenating benefits and can soften fine lines and wrinkles, lighten mottled hyperpigmentation, improve skin roughness, sallowness, and overall appearance of photoaged skin. Retinoic acid or tretinoin remains favored among dermatologists because there are a plethora of well‐designed clinical trials confirming its efficacy as a topical therapy for treating aging skin. In contrast, cosmeceutical retinoids are regulated as cosmetics and in general are not subjected to the same degree of scientific rigor as prescription retinoids. Despite this difference, there are studies confirming the antiaging benefits of cosmeceutical retinoids and studies comparing their efficacy and tolerability to tretinoin. This review will focus on over‐the‐counter retinoids including retinol, retinaldehyde, retinyl esters, adapalene, and novel retinoid molecules. Studies on pharmacokinetics, mechanisms of action, clinical benefits, and tolerability will be reviewed.

27862 Trifarotene transcriptomics analysis and acne-related gene expression

Trifarotene cream, 0.005% is an FDA approved topical retinoid indicated for treatment of facial and truncal acne and has received positive outcome through the European Decentralized Procedure. Trifarotene is the first novel topical retinoid molecule approved for acne treatment in 20 years, and the only approved retinoid that specifically acts through retinoic acid receptor gamma. This study investigated new potential pathways through which trifarotene exerts its efficacy in acne by analyzing the changes in gene expression in the skin of acne patients. Subjects with moderate inflammatory acne of the back were treated with trifarotene 0.005% or vehicle cream on dedicated back areas for 27 days, and 4 biopsies were collected on each subject (non-involved skin, acne papule, trifarotene, and vehicle-treated site). Large-scale gene expression profiling of the biopsies was performed using Affymetrix technology, and treatment specific gene expression profiles were generated using statistical modeling. This analysis highlighted a specific gene expression profile, comprising of 67 genes uniquely driven by Trifarotene treatment with most of these genes known to affect immune responses as well as extracellular matrix reorganization. Interestingly, those genes were downregulated as compared with the papule signature suggesting that trifarotene reverses some inflammatory processes of the papule. Altogether, these results show that trifarotene has a unique action in acne treatment by acting on epidermal differentiation and proliferation (Aubert et al., 2018) as well as on innate and adaptive immune cells in acne pathogenesis.

Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells

The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.

Zymbilan®-PSO cream with nano-encapsulated RetileX-A®-PRO mitigates the clinical severity and relieves the symptoms of chronic plaque psoriasis: an interventional clinical study

<p><strong>Background:</strong> Skin psoriasis is a serious inflammatory disorder with increased risk of rheumatic, cardiometabolic and psychosocial complications. At present, >50% of patients are dissatisfied with their treatment; thus, novel approaches are in high clinical demand. Retinoids are a major group of anti-psoriatic compounds; nonetheless, dose-dependent topical side effects have limited their effective topical application. RetileX-A<sup>®</sup>-PRO (Pharma Medico, Aarhus, Denmark) is a novel nano-encapsulated retinol ester designed to minimise the risk of skin irritation. The proprietary nano-encapsulation technology used in this compound can protect retinoid molecules from degradation, and thereby prolong and stabilise its release profile. The safety and efficacy of RetileX-A<sup>®</sup>-PRO were evaluated in this study.</p><p><strong>Methods:</strong> 45 patients (58% female, aged 18-80 years) with mild to moderate skin psoriasis were enrolled in a 4-week interventional study. Participants were treated once daily with Zymbilan<sup>®</sup>-PSO cream with RetileX-A<sup>®</sup>-PRO and evaluated both objectively and subjectively at baseline, after 8 hours and at endpoint.</p><p><strong>Results:</strong> Our observations demonstrated that Zymbilan<sup>®</sup>-PSO cream possesses both short-term and long-term anti-psoriatic effects. Shortly after application, objective skin characteristics were improved, and itching reduced in >84% of subjects. At endpoint, 87% of skin lesions improved, 9% did not change and 4% progressed as assessed by a dermatologist. Patients’ self-evaluation yielded similar results: 78% judged Zymbilan<sup>®</sup>-PSO cream as a ‘good’ to ‘very good’ skin care product with suitable cosmetic parameters. No side effects recorded in 95% of participants.</p><p><strong>Conclusions:</strong> In conclusion, Zymbilan<sup>®</sup>-PSO cream is a well-tolerated treatment that can mitigate both clinical severity and subjective symptoms of chronic skin psoriasis.</p>

Ultrasensitive Vibrational Imaging of Retinoids by Visible Preresonance Stimulated Raman Scattering Microscopy.

High‐sensitivity chemical imaging offers a window to decipher the molecular orchestra inside a living system. Based on vibrational fingerprint signatures, coherent Raman scattering microscopy provides a label‐free approach to map biomolecules and drug molecules inside a cell. Yet, by near‐infrared (NIR) pulse excitation, the sensitivity is limited to millimolar concentration for endogenous biomolecules. Here, the imaging sensitivity of stimulated Raman scattering (SRS) is significantly boosted for retinoid molecules to 34 micromolar via electronic preresonance in the visible wavelength regime. Retinoids play critical roles in development, immunity, stem cell differentiation, and lipid metabolism. By visible preresonance SRS (VP‐SRS) imaging, retinoid distribution in single embryonic neurons and mouse brain tissues is mapped, retinoid storage in chemoresistant pancreatic and ovarian cancers is revealed, and retinoids stored in protein network and lipid droplets of Caenorahbditis elegans are identified. These results demonstrate VP‐SRS microscopy as an ultrasensitive label‐free chemical imaging tool and collectively open new opportunities of understanding the function of retinoids in biological systems.

Subject Satisfaction with Trifarotene 50 μg/g Cream in the Treatment of Facial and Truncal Acne Vulgaris: A Case Series

There is a paucity of literature covering patient-reported outcomes of treatments for truncal acne. Trifarotene 50 μg/g cream is a novel retinoid molecule approved for once-daily topical treatment of facial and truncal acne vulgaris. As physicians are starting to gain real-world experience with this retinoid treatment, their access to reporting from the patient’s perspective provides a valuable adjunct to the pivotal studies. We report a case series of three subjects with moderate facial and truncal acne treated with trifarotene 50 μg/g cream on the face, shoulders, upper back and upper anterior chest for 12 weeks and evaluated by satisfaction questionnaires. This case series illustrating the treatment of facial and truncal acne with trifarotene 50 μg/g cream, in the form of real-world data, describes high overall satisfaction and excellent tolerability to support the use of this new retinoid molecule in the treatment of acne vulgaris on both the face and trunk.

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies.

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs. The RAR receptors control the homeostasis of tissue growth, modeling and regeneration, and PML-NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. The additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. The treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. The resistance to ATRA and ATO may derive from the mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5–10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or the induction of apoptosis in APL cells.

Tucumã extracts decreases PML/RARΑ gene expression in NB4/APL cell line

Acute promyelocytic leukemia (APL) is a cancer pharmacologically treated with all-trans retinoic acid (ATRA), although well tolerated by most patients, some develop toxicity to ATRA, Differentiation Syndrome. The Amazon Biome has several fruits and oil plants rich in micronutrients, particularly carotenoids as the fruit tucumã (Astrocaryum aculeatum). This study analyzed the antitumor and cytoprotective activity of tucumã with and without concomitant exposure of ATRA in high concentration mimicking the toxicity of differentiation syndrome, as the potential cytotoxic effect of chemotherapeutic in an APL cell line. The cultured NB4 cells were exposed to ethanolic extracts of tucumã and to synergism with extracts and ATRA. Determination of proliferation, cell viability, caspases 1, 3, 8 and cell differentiation by nested RT-qPCR. The ATRA control had a strong inhibitory effect and toxicity as expected. The extracts also reduced cell proliferation by triggering apoptosis in concentration-dependent and reversing chromosome translocation, especially the lowest tested concentration of tucumã pulp extract. In the synergism, extracts act to maintain the levels of viability and apoptosis equal to the ATRA control but in contrast to drug that causes death and destruction of the genetic material, tucumã demonstrated a reduction of the gene expression indicating a possible protection against the toxicity of high concentrations of ATRA. These results suggest that fruits rich in retinoid molecules may have a cytotoxic effect against APL cells and reduced concentrations of carotenoids may act as cytoprotectors in APL cells treated with high concentrations of ATRA promoting cellular/molecular differentiation.

Ultrafast photoisomerisation of an isolated retinoid.

The photoinduced excited state dynamics of gas-phase trans-retinoate (deprotonated trans-retinoic acid, trans-RA-) are studied using tandem ion mobility spectrometry coupled with laser spectroscopy, and frequency-, angle- and time-resolved photoelectron imaging. Photoexcitation of the bright S3(ππ*) ← S0 transition leads to internal conversion to the S1(ππ*) state on a ≈80 fs timescale followed by recovery of S0 and concomitant isomerisation to give the 13-cis (major) and 9-cis (minor) photoisomers on a ≈180 fs timescale. The sub-200 fs stereoselective photoisomerisation parallels that for the retinal protonated Schiff base chromophore in bacteriorhodopsin. Measurements on trans-RA- in methanol using the solution photoisomerisation action spectroscopy technique show that 13-cis-RA- is also the principal photoisomer, although the 13-cis and 9-cis photoisomers are formed with an inverted branching ratio with photon energy in methanol when compared with the gas phase, presumably due to solvent-induced modification of potential energy surfaces and inhibition of electron detachment processes. Comparison of the gas-phase time-resolved data with transient absorption spectroscopy measurements on retinoic acid in methanol suggest that photoisomerisation is roughly six times slower in solution. This work provides clear evidence that solvation significantly affects the photoisomerisation dynamics of retinoid molecules.

Spin in a Closed-Shell Organic Molecule on a Metal Substrate Generated by a Sigmatropic Reaction.

Inert metal surfaces present more chances of hosting organic intact radicals than other substrates, but large amounts of delocalized electronic states favor charge transfer and thus spin quenching. Lowering the molecule-substrate interaction is a usual strategy to stabilize radicals on surfaces. In some works, thin insulating layers were introduced to provide a controllable degree of electronic decoupling. Recently, retinoid molecules adsorbed on gold have been manipulated with a scanning tunneling microscope (STM) to exhibit a localized spin, but calculations failed to find a radical derivative of the molecule on the surface. Now the formation of a neutral radical spatially localized in a tilted and lifted cyclic end of the molecule is presented. An allene moiety provokes a perpendicular tilt of the cyclic end relative to the rest of the conjugated chain, thus localizing the spin of the dehydrogenated allene in its lifted subpart. DFT calculations and STM manipulations give support to the proposed mechanism.

Spin in a Closed‐Shell Organic Molecule on a Metal Substrate Generated by a Sigmatropic Reaction

AbstractInert metal surfaces present more chances of hosting organic intact radicals than other substrates, but large amounts of delocalized electronic states favor charge transfer and thus spin quenching. Lowering the molecule–substrate interaction is a usual strategy to stabilize radicals on surfaces. In some works, thin insulating layers were introduced to provide a controllable degree of electronic decoupling. Recently, retinoid molecules adsorbed on gold have been manipulated with a scanning tunneling microscope (STM) to exhibit a localized spin, but calculations failed to find a radical derivative of the molecule on the surface. Now the formation of a neutral radical spatially localized in a tilted and lifted cyclic end of the molecule is presented. An allene moiety provokes a perpendicular tilt of the cyclic end relative to the rest of the conjugated chain, thus localizing the spin of the dehydrogenated allene in its lifted subpart. DFT calculations and STM manipulations give support to the proposed mechanism.

Electrochemical Study and Determination of All-trans-Retinol at Carbon Paste Electrode Modified by a Surfactant.

SummaryThe oxidation mechanism of all-trans-retinol (vitamin A1) and its several esters in non-aqueous, aqueous organic mixture, and pure aqueous media was investigated by cyclic voltammetry. The oxidation occurred in several irreversible steps. The calculated highest density of electrons in retinoid molecules which are delocalized over carbon atoms of the five conjugated double bonds (C5-C14) was found in the part of the molecule involved in oxidation processes. The most sensitive oxidation peak (at +0.8 V vs. Ag/AgCl) was used for development of new direct voltammetric method based on differential pulse voltammetry for the determination of retinol at carbon paste electrode modified with surfactant sodium dodecyl sulfate (CPE/SDS). The results show that 30% (by mass) of modifier SDS exhibited optimal sensitivity and shape of voltammograms. Compared to commonly used glassy carbon electrode (GCE), the CPE/SDS showed significant progress in the retinol electroanalysis. The linear ranges for retinol determination were 1.5·10−6–1.8·10−4 M for CPE/SDS and 4.4·10−6–7.0·10−4 M for GCE with the detection limits of 1.3·10−6 and 4.6·10−7 M, respectively.

A robust and reproducible human pluripotent stem cell derived model of neurite outgrowth in a three-dimensional culture system and its application to study neurite inhibition

The inability of neurites to grow and restore neural connections is common to many neurological disorders, including trauma to the central nervous system and neurodegenerative diseases. Therefore, there is need for a robust and reproducible model of neurite outgrowth, to provide a tool to study the molecular mechanisms that underpin the process of neurite inhibition and to screen molecules that may be able to overcome such inhibition. In this study a novel in vitro pluripotent stem cell based model of human neuritogenesis was developed. This was achieved by incorporating additional technologies, notably a stable synthetic inducer of neural differentiation, and the application of three-dimensional (3D) cell culture techniques. We have evaluated the use of photostable, synthetic retinoid molecules to promote neural differentiation and found that 0.01 μM EC23 was the optimal concentration to promote differentiation and neurite outgrowth from human pluripotent stem cells within our model. We have also developed a methodology to enable quick and accurate quantification of neurite outgrowth derived from such a model. Furthermore, we have obtained significant neurite outgrowth within a 3D culture system enhancing the level of neuritogenesis observed and providing a more physiological microenvironment to investigate the molecular mechanisms that underpin neurite outgrowth and inhibition within the nervous system. We have demonstrated a potential application of our model in co-culture with glioma cells, to recapitulate aspects of the process of neurite inhibition that may also occur in the injured spinal cord. We propose that such a system that can be utilised to investigate the molecular mechanisms that underpin neurite inhibition mediated via glial and neuron interactions.

Cis-retinoids and the chemistry of vision

We discuss here principal biochemical transformations of retinoid molecules in the visual cycle. We focus our analysis on the accumulating evidence of alternate pathways and functional redundancies in the cycle. The efficiency of the visual cycle depends, on one hand, on fast regeneration of the photo-bleached chromophores. On the other hand, it is crucial that the cyclic process should be highly selective to avoid accumulation of byproducts. The state-of-the-art knowledge indicates that single enzymatically active components of the cycle are not strictly selective and may require chaperones to enhance their rates. It appears that protein–protein interactions significantly improve the biological stability of the visual cycle. In particular, synthesis of thermodynamically less stable 11-cis-retinoid conformers is favored by physical interactions of the isomerases present in the retina with cellular retinaldehyde binding protein.

Locating the binding sites of retinol and retinoic acid with milk β-lactoglobulin

β-lactoglobulin (β-LG) is a member of lipocalin superfamily of transporters for small hydrophobic molecules such as retinoids. We located the binding sites of retinol and retinoic acid on β-LG in aqueous solution at physiological conditions, using FTIR, CD, fluorescence spectroscopic methods, and molecular modeling. The retinoid-binding sites and the binding constants as well as the effect of retinol and retinoic acid complexation on protein stability and secondary structure were determined. Structural analysis showed that retinoids bind strongly to β-LG via both hydrophilic and hydrophobic contacts with overall binding constants of K retinol- β -LG = 6.4 (± .6) × 106 M−1 and K retinoic acid- β -LG = 3.3 (± .5) × 106 M−1. The number of retinoid molecules bound per protein (n) is 1.1 (± .2) for retinol and 1.5 (± .3) for retinoic acid. Molecular modeling showed the participation of several amino acids in the retinoid–protein complexes with the free binding energy of −8.11 kcal/mol for retinol and −7.62 kcal/mol for retinoic acid. Protein conformation was altered with reduction of β-sheet from 59 (free protein) to 52–51% and a major increase in turn structure from 13 (free protein) to 24–22%, in the retinoid–β-LG complexes, indicating a partial protein destabilization.

Retinoid-Binding Proteins: Similar Protein Architectures Bind Similar Ligands via Completely Different Ways

BackgroundRetinoids are a class of compounds that are chemically related to vitamin A, which is an essential nutrient that plays a key role in vision, cell growth and differentiation. In vivo, retinoids must bind with specific proteins to perform their necessary functions. Plasma retinol-binding protein (RBP) and epididymal retinoic acid binding protein (ERABP) carry retinoids in bodily fluids, while cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs) carry retinoids within cells. Interestingly, although all of these transport proteins possess similar structures, the modes of binding for the different retinoid ligands with their carrier proteins are different.Methodology/Principal FindingsIn this work, we analyzed the various retinoid transport mechanisms using structure and sequence comparisons, binding site analyses and molecular dynamics simulations. Our results show that in the same family of proteins and subcellular location, the orientation of a retinoid molecule within a binding protein is same, whereas when different families of proteins are considered, the orientation of the bound retinoid is completely different. In addition, none of the amino acid residues involved in ligand binding is conserved between the transport proteins. However, for each specific binding protein, the amino acids involved in the ligand binding are conserved. The results of this study allow us to propose a possible transport model for retinoids.Conclusions/SignificanceOur results reveal the differences in the binding modes between the different retinoid-binding proteins.

Binding sites of retinol and retinoic acid with serum albumins

Retinoids are effectively transported in the bloodstream via serum albumins. We report the complexation of bovine serum albumin (BSA) with retinol and retinoic acid at physiological conditions, using constant protein concentration and various retinoid contents. FTIR, CD and fluorescence spectroscopic methods and molecular modeling were used to analyze retinoid binding site, the binding constant and the effects of complexation on BSA stability and secondary structure. Structural analysis showed that retinoids bind BSA via hydrophilic and hydrophobic interactions with overall binding constants of K Ret –BSA = 5.3 (±0.8) × 10 6 M −1 and K Retac –BSA = 2.3 (±0.4) × 10 6 M −1. The number of bound retinoid molecules ( n) was 1.20 (±0.2) for retinol and 1.8 (±0.3) for retinoic acid. Molecular modeling showed the participation of several amino acids in retinoid–BSA complexes stabilized by H-bonding network. The retinoid binding altered BSA conformation with a major reduction of α-helix from 61% (free BSA) to 36% (retinol–BSA) and 26% (retinoic acid–BSA) with an increase in turn and random coil structures indicating a partial protein unfolding. The results indicate that serum albumins are capable of transporting retinoids in vitro and in vivo.

Maximal adamantyl-substituted retinoid-related molecule-induced apoptosis requires NF-κB noncanonical and canonical pathway activation

NF-κB transcription factors have a critical role in regulating cell survival and apoptosis. We have previously shown that 4-(3-Cl-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid (3-Cl-AHPC), an adamantyl-substituted retinoid molecule, induced apoptosis and required NF-κB activation in prostate and breast carcinoma cells. Here, we show that 3-Cl-AHPC activated both IκB kinase (IKK)α and IKKβ with subsequent activation of the canonical and noncanonical NF-κB pathways in the human breast carcinoma and leukemia cell lines. 3-Cl-AHPC-mediated activation of the NF-κB canonical pathway occurred within 6 h, whereas maximal activation of the NF-κB noncanonical pathway required 48 h. Knockout of IKKα or IKKβ expression in mouse embryonic fibroblast cells and knockdown of IKKα or IKKβ in MDA-MB-468 cells resulted in the inhibition of 3-Cl-AHPC-mediated apoptosis, indicating that activation of canonical and noncanonical pathways are required for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC activation of the noncanonical pathway was preceded by caspase-mediated decrease in the E3-ligase c-IAP1 with subsequent stabilization of NF-κB-inducing kinase (NIK) expression, increased binding of NIK by TRAF3, activation of IKKα, and the resultant increased levels of RelB and p52. Increased expression of c-IAP1 blocked 3-Cl-AHPC-mediated stabilization of NIK levels and 3-Cl-AHPC-mediated apoptosis. Cdc37 expression was required for activation of IKKα and IKKβ by 3-Cl-AHPC. These findings suggest that NF-κB pathways have an important role in 3-Cl-AHPC-mediated apoptosis.

Effects of methyl derivatives of the rexinoid UAB30 on methylnitrosourea (MNU) induced mammary cancers and on various indicators of toxicity.

Abstract Abstract #1108 UAB30 is a RXR selective retinoid that has shown excellent activity in preventing chemically-induced mammary cancers with minimal toxicity (specifically not increasing serum triglycerides), and is currently undergoing a Phase I clinical trial. Several methyl analogs were synthesized in an attempt to obtain a more active preventive agent and to better understand the mechanisms of activity/toxicity of this class of agents. The retinoids included 4-methyl-UAB30, 5-methyl-UAB30, 6-methyl-UAB30, 7-methyl-UAB30, and 8-methyl-UAB30. The compounds were evaluated in the MNU-induced mammary cancer model using female Sprague-Dawley rats. MNU (75 mg/kg BW) was administered at 50 days of age and the animals observed for 120 days afterward for the development of ER+ mammary cancers. The retinoids were given at a dose of 200 mg/kg diet, except 7-methyl-UAB30 (given at 100 mg/kg diet). 4-Methyl-UAB30 and 7-methyl-UAB30 were highly active; reducing mammary cancer multiplicity by 74 and 61%, respectively. The retinoids 5-methyl-UAB30, 6-methyl-UAB30, and 8-methyl-UAB30 did not have chemopreventive activity in this model. The 8-methyl-UAB30 derivative actually caused a 108% increase in growth of the mammary cancers. As we have previously shown (Carcinogenesis 27, 1232-1239, 2006), serum triglycerides correlated with cancer preventive activity; i.e., high levels were observed with active retinoids. 4-methyl-UAB30 caused an initial large increase in body weight gain of the rats. Of interest, serum levels of 6-methyl-UAB30 and 7-methyl-UAB30 were high, while the other agents were low or could not be detected. All methyl derivatives caused varying decreases in liver retinyl palmitate levels. Structure-activity relationships are also being evaluated using crystallography of RXR/UAB-rexinoid complexes as a guide. Structure-based and dynamic-based approaches are used to facilitate the design of new rexinoids that fit into the LBD of RXRs. For example, 4-methyl-UAB30 had a 5-fold greater binding affinity to hRXR alpha LBD than 9-cis-retinoic-acid. These studies emphasize that minor modifications of a retinoid molecule can drastically change its absorption, metabolism, toxicity, binding affinities to receptors, and activity in preventing mammary cancers. (Supported by NCI Breast SPORE CA089019 and contract HHSN261200433001C). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1108.