Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans

1994 ◽  
Vol 30 (3) ◽  
pp. 428-434 ◽  
Author(s):  
Peter Buchan ◽  
Christian Eckhoff ◽  
Danièle Caron ◽  
Heinz Nau ◽  
Braham Shroot ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Plasma Levels ◽  
Topical Administration ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Retinoic Acids in the Treatment of Most Lethal Solid Cancers

2020 ◽  
Vol 9 (2) ◽  
pp. 360 ◽  
Author(s):  
Lara Costantini ◽  
Romina Molinari ◽  
Barbara Farinon ◽  
Nicolò Merendino
Keyword(s):  
Retinoic Acid ◽  
World Health ◽  
Solid Cancer ◽  
Molecular Pathways ◽  
Acid Therapy ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cancer Types ◽  
Health Organization

Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

Chemokine Induction by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia - Triggering the Retinoic Acid Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2980-2980
Author(s):  
Maaike Luesink ◽  
Jeroen Pennings ◽  
Willemijn Wissink ◽  
Peter Linssen ◽  
Petra Muus ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Plasma Levels ◽  
Promyelocytic Leukemia ◽  
Inflammatory Cascade ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cc Chemokines ◽  
Retinoic Acid Syndrome

Abstract The most important complication of all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) is the retinoic acid syndrome (RAS), a life-threatening hyper-inflammatory reaction with a distinct capillary leak syndrome and multi-organ failure. Once established, the syndrome has proven very difficult to manage. Early recognition in combination with prompt corticosteroid treatment significantly reduces the mortality rate of patients with this syndrome. Nonetheless, still 15% of the induction deaths in APL is caused by RAS. The pathogenic mechanism of the hyper-inflammatory cascade in RAS is not fully understood yet. Infiltration of differentiating APL cells in the lung is important in the development of RAS. In addition, differentiation of APL cells by ATRA is associated with increased expression and release of pro-inflammatory cytokines, chemokines and adhesion molecules in vitro and it has been hypothesized that this is important for the triggering of the hyper-inflammatory cascade in RAS. We investigated the effect of ATRA on the expression and secretion of chemokines in APL cells in vitro and in vivo. Using microarray, quantitative PCR and ELISA we demonstrated significant induction (up to 16000-fold) of 8 CC-chemokines (CCLs) in the NB4 APL cell line after differentiation induction with ATRA in vitro. To demonstrate the significance of chemokine induction by ATRA in vivo, we measured plasma levels of CCLs in 3 APL patients, treated with a combination of ATRA, idarubicine and prednisone according to the AIDA-2000/P protocol. One of these patients developed an obvious retinoic acid syndrome. During therapy we observed increased plasma levels of 3 CCLs in all three patients. Induction of 5 other CCLs (CCL3, CCL4, CCL7, CCL8, CL11) was only observed during RAS, suggesting that upregulation of these 5 CC-chemokines is specific for RAS. To investigate whether the plasma levels of CC-chemokines are functionally relevant, we measured chemo-attraction of peripheral blood leukocytes towards plasma of an APL patient who developed RAS using a transwell system. Plasma from this patient during RAS showed significant more chemo-attraction than plasma from the same patient before treatment with ATRA, idarubicine and prednisone. Subsequently we investigated whether the therapeutic effect of dexamethasone in RAS can be ascribed to downregulation of chemokine expression in APL cells. Despite dexamethasone, the induction of chemokine expression in NB4 cells by ATRA sustained. We conclude that ATRA causes massive secretion of chemokines by APL cells, which might trigger the hyper-inflammatory cascade in RAS by continuous attraction of APL cells and other inflammatory cells towards tissues like the lung. Dexamethasone does not abrogate the production of CC-chemokines by APL cells, but rather seems to inhibit the hyper-inflammatory cascade at the level of the effector cells and target tissues like the lung. This might explain why dexamethasone is not able to sufficiently reverse a retinoic acid syndrome once it has been established. The application of neutralizing CC-chemokine receptor antibodies or other antagonists might be an alternative route to treat an established retinoic acid syndrome.

Olfactomedin 4 Mediates All-Trans Retinoic Acid Induced Growth Inhibition, Differentiation and Apoptosis in Myeloid Leukemia Cells and Inhibits 4E-BP1 Phosphorylation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2395-2395
Author(s):  
Wenli Liu ◽  
Hyun W Lee ◽  
Griffin P Rodgers
Keyword(s):  
Retinoic Acid ◽  
Chronic Myeloid Leukemia ◽  
Growth Inhibition ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Over Expression ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Novel Target

Abstract Abstract 2395 Poster Board II-372 Introduction: All-trans retinoic acid (ATRA) has been shown to induce cellular differentiation and growth inhibition of acute promyelocytic leukemia cells. Clinical application of ATRA has proved extremely successful in inducing clinical remission in most acute promyelocytic leukemia patients. Although the mechanisms of retinoid-dependent gene transcription regulation are well understood, the target genes that mediate retinoid-induced biological responses still remain to be defined. Olfactomedin 4 (OLFM4, also called hGC-1 and GW112) is a member of olfactomedin-related glycoprotein family. It is constitutively expressed in myeloid cells and gastrointestinal tract. It has been recently reported that OLFM4 expression is up-regulated in stomach and colon cancer patients. The purpose of this study is to examine its expression in myeloid leukemia patients, its regulation by ATRA and potential biological functions in myeloid leukemia. Results: 1) In this study, we found that OLFM4 expression was up-regulated in the peripheral leukocytes of chronic myeloid leukemia patients (91%, 22 cases) and acute myeloid leukemia patients (30%, 10 cases). OLFM4 expression in accelerated phase of chronic myeloid leukemia patients was significantly higher than that in chronic phase. 2) We identified that OLFM4 is a novel target gene of retinoic acids in myeloid leukemia cells. Treatment of HL-60 cells with ATRA and 9-cis-RA induced OLFM4 expression. The expression level of OLFM4 is correlated with the myeloid cell differentiation stage. Deletion analysis led to the identification of a positive retinoic acid response element (DR5) and a negative response element (DR1) within OLFM4 promoter. Furthermore, electrophoretic mobility-shift assays and transfection study in COS-7 cells demonstrated that RARα/RXRα binds to the DR5 site and mediates ATRA induced transactivation of OLFM4 promoter. 3) We showed that OLFM4 over-expression in HL-60 cells lead to growth inhibition, differentiation and apoptosis and potentates ATRA mediated these effects. Conversely, silencing of endogenous OLFM4 by lentiviral shRNA against OLFM4 in AML-193 cells reduces ATRA induced growth inhibition, differentiation and apoptosis. 4) We further investigated the molecular mechanism that OLFM4 is involved in leukemia cell growth and differentiation. We found that over-expression of OLFM4 in HL60 cells inhibited ATRA induced phosphorylation of translation repressor 4E-BP1. This inhibitory effect was further confirmed in 293T cells, in which over-expression of OLFM4 inhibits 4E-BP1 phosphorylation at all four phosphorylation sites (Thr37/46, Thr70 and Ser65). Application of lentiviral shRNA against OLFM4 in AML-193 increased phosphorylation of 4E-BP1 compared with control shRNA. Over-expression of OLFM4 in HL60 cells does not affect phosphorylation of Akt, p70S6 kinase, GSK3β and ERK1/2 . Conclusion: 1) OLFM4 expression is up-regulated in chronic and acute myeloid leukemia patients and is correlated with the stage of chronic myeloid leukemia. 2) OLFM4 is a novel target gene of retinoic acids. RARα/RXRα binds to the DR5 site of OLFM4 promoter and mediates the ATRA induced transactivation of OLFM4. 3) OLFM4 mediates ATRA induced growth inhibition, differentiation and apoptosis of myeloid leukemia cells. 4) OLFM4 acts an inhibitor of 4E-BP1 phosphorylation down stream of Akt and mTOR, suggesting OLFM4 may inhibit protein synthesis that is observed with the differentiation of myeloid leukemia cells. Our results suggest that OLFM4 up-regulation in the leukocytes of leukemia patients might have a feedback effect to restrain cell growth, and induce differentiation and apoptosis rather than act as an initiator of leukemiagenesis. As OLFM4 is a secreted glycoprotein, it could represent a promising therapeutic agent in the treatment of myeloid leukemia patients. The effect of purified OLFM4 on leukemia cells is currently under investigation. Disclosures: No relevant conflicts of interest to declare.

CATALYTIC MECHANISM OF ALL-TRANS-RETINOIC ACID 4-HYDROXYLATION MEDIATED BY CYTOCHROME P450 2C8: HOW DOES ARGININE 241 AFFECT THE C–H BOND ACTIVATION?

2013 ◽  
Vol 12 (08) ◽  
pp. 1341009
Author(s):  
XIAO-XI LI ◽  
JI-LONG ZHANG ◽  
QING-CHUAN ZHENG ◽  
YING-LU CUI ◽  
RUI-JUAN NIU ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Reaction Mechanism ◽  
Binding Sites ◽  
Bond Activation ◽  
Salt Bridge ◽  
Hydrogen Atom Transfer ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cytochrome P450 2C8

Experiments revealed that cytochrome P450 2C8 enzyme (CYP2C8) has two distinct substrate binding sites to the physiologically important molecules, retinoic acids, and the main difference between these two binding sites is whether there is a salt bridge interaction between the anionic carboxylate tail of retinoic acids and the surrounding protein environment. However, the influence of such salt bridge interaction toward catalysis is still elusive. In the present paper, density functional theory (DFT) calculations were employed to research the reaction mechanism of all-trans-retinoic acid (atRA) 4-hydroxylation mediated by CYP2C8. Our DFT calculations revealed that such salt bridge interaction has obvious effects on the reaction mechanism of atRA 4-hydroxylation. In the binding site containing a salt bridge interaction between the anionic carboxylate tail of atRA and the cationic guanidine group of Arg241, C – H bond activation proceeds via a normal hydrogen atom transfer (HAT) mechanism; in the other site without this salt bridge interaction, however, C – H bond activation is achieved via a stepwise electron transfer and hydrogen atom transfer, thus, a novel ET/HAT mechanism. These findings enrich the mechanism patterns of C – H bond activation catalyzed by metalloenzymes and their biomimetics. Meanwhile, the self-interaction error (SIE) problem encountered during our calculations in vacuum was affected and removed by the inclusion of an external electric field in the calculations.

scholarly journals Reduced Carotenoid and Retinoid Concentrations and Altered Lycopene Isomer Ratio in Plasma of Atopic Dermatitis Patients

2018 ◽  
Author(s):  
Renata Lucas ◽  
Johanna Mihaly ◽  
Gordon M. Lowe ◽  
Daniel L. Graham ◽  
Monika Szklenar ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Retinoic Acid ◽  
Plasma Levels ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Human Organism ◽  
Isomer Ratio ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

In the human organism various carotenoids are present of which, some are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors like the retinoic acid receptor and the retinoid X receptor. In our study using an HPLC analytical approach we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n=20) compared to healthy volunteers (HV, n=20). We found that plasma levels of the carotenoids lutein (HV 198 ± 68 ng/ml, AD 158 ± 57 ng/ml), zeaxanthin (HV 350 ± 142 ng/ml, AD 236 ± 85) as well as the retinoids retinol (HV 216 ± 89 ng/ml, AD 167 ± 76 ng/ml) and all-trans-retinoic acid (HV 1.1 ± 0.6 ng/ml, AD 0.7 ± 0.5 ng/ml) were significantly lower in AD-patients, while lycopene, α-carotene and β-carotene levels were comparable. In addition the ratios of 13-cis vs. all-trans lycopene as well as 13-cis vs. all-trans retinoic acid were increased in the plasma of AD-patients indicating an AD-specific 13C-isomerisation. A positive correlation with SCORRAD was calculated with 13-cis vs. all-trans lycopene ratio, while a negative correlation was observed with zeaxanthin plasma levels. Based on our results we conclude that in the plasma of AD-patients various carotenoids and retinoids are at lower levels, while the ratio of lycopene isomers was also altered. The higher rate of lycopene and retinoic acid isomerisation products might be a consequence of AD or might result in an altered activation of nuclear hormone receptor signaling pathways and thus maybe partly be responsible for the AD-phenotype and additionally may represent a good plasma marker for AD.

scholarly journals Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review

2018 ◽  
Vol 19 (11) ◽  
pp. 3388 ◽  
Author(s):  
Damien Bouriez ◽  
Julie Giraud ◽  
Caroline Gronnier ◽  
Christine Varon
Keyword(s):  
Gastric Cancer ◽  
Retinoic Acid ◽  
Remission Rate ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Narrative Literature ◽  
Xenograft Mice ◽  
Narrative Literature Review ◽  
Cluster Of Differentiation

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new targeted therapies. Those CSCs express biomarkers such as cluster of differentiation 44 (CD44) and display high aldehyde dehydrogenase activity that converts vitamin A-derived retinal into retinoic acids. All-trans retinoic acid (ATRA), which has pro-differentiating properties, has revolutionized the prognosis of acute promyelotic leukemia by increasing its remission rate from 15% to 85%. Recent studies have started to show that ATRA also has an anti-tumoral role on solid cancers such as GC. The purpose of this review is therefore to summarize the work that evaluated the effects of ATRA in GC and to evaluate whether its anti-cancerous action involves gastric CSCs targeting. It has been demonstrated that ATRA can block the cell cycle, enhance apoptosis, and decrease gastric CSCs properties in GC cell lines, tumorspheres, and patient-derived xenograft mice models. Therefore, retinoids and new synthetic retinoids seem to be a promising step forward in targeted therapy of gastric CSC in combination with existing chemotherapies. Future studies should probably focus on these points.

scholarly journals Reduced Carotenoid and Retinoid Concentrations and Altered Lycopene Isomer Ratio in Plasma of Atopic Dermatitis Patients

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1390 ◽  
Author(s):  
Renata Lucas ◽  
Johanna Mihály ◽  
Gordon Lowe ◽  
Daniel Graham ◽  
Monika Szklenar ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Retinoic Acid ◽  
Healthy Volunteers ◽  
Plasma Levels ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Human Organism ◽  
Isomer Ratio ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Carotenoids and retinoids are known to alter the allergic response with important physiological roles in the skin and the immune system. In the human organism various carotenoids are present, some of which are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors such as the retinoic acid receptor and the retinoid X receptor. In this study, we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n = 20) compared to healthy volunteers (HV, n = 20). The study indicated that plasma levels of the carotenoids lutein (HV 198 ± 14 ng/mL, AD 158 ± 12 ng/mL, p = 0.02; all values in mean ± SEM), zeaxanthin (HV 349 ± 30 ng/mL, AD 236 ± 18 ng/mL, p ≤ 0.01), as well as the retinoids retinol (HV 216 ± 20 ng/mL, AD 167 ± 17 ng/mL, p = 0.04) and all-trans-retinoic acid (HV 1.1 ± 0.1 ng/mL, AD 0.7 ± 0.1 ng/mL, p = 0.04) were significantly lower in the AD-patients, while lycopene isomers, α-carotene, and β-carotene levels were comparable to that determined in the healthy volunteers. In addition, the ratios of 13-cis- vs. all-trans-lycopene (HV 0.31 ± 0.01, AD 0.45 ± 0.07, p = 0.03) as well as 13-cis- vs. all-trans-retinoic acid (HV 1.4 ± 0.2, AD 2.6 ± 0.6, p = 0.03) were increased in the plasma of AD-patients indicating an AD-specific 13-cis-isomerisation. A positive correlation with SCORAD was calculated with 13-cis- vs. all-trans-lycopene ratio (r = 0.40, p = 0.01), while a negative correlation was observed with zeaxanthin plasma levels (r = −0.42, p = 0.01). Based on our results, we conclude that in the plasma of AD-patients various carotenoids and retinoids are present at lower concentrations, while the ratio of selected lycopene isomers also differed in the AD-patient group. An increase in plasma isomers of both lycopene and retinoic acid may cause an altered activation of nuclear hormone receptor signaling pathways and thus may be partly responsible for the AD-phenotype.

scholarly journals A novel isoenzyme of aldehyde dehydrogenase specifically involved in the biosynthesis of 9-cis and all-trans retinoic acid

1995 ◽  
Vol 305 (2) ◽  
pp. 681-684 ◽  
Author(s):  
J Labrecque ◽  
F Dumas ◽  
A Lacroix ◽  
P V Bhat
Keyword(s):  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
High Efficiency ◽  
Rat Kidney ◽  
Ph Optimum ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
X Receptors ◽  
Specific Ligand

The pleiotropic effects of retinoids are mediated by two families of nuclear receptors: RAR (retinoic acid receptors) and RXR (retinoid X receptors). 9-cis-Retinoic acid is a specific ligand for RXR receptors, whereas either 9-cis- or all-trans-retinoic acid activates the RAR receptor family. The existence of RXRs suggests a new role for isomerization in the biology of retinoic acid. We report here the identification of an aldehyde dehydrogenase in the rat kidney that catalysed the oxidation of 9-cis- and all-trans-retinal to corresponding retinoic acids with high efficiency, 9-cis-retinal being 2-fold more active than all-trans-retinal. Based on several criteria, such as amino acid sequence, pH optimum, and inhibition by chloral hydrate, this enzyme was found to be a novel isoenzyme of aldehyde dehydrogenase. 9-cis-Retinol, the precursor for the biosynthesis of 9-cis-retinal was identified in the rat kidney. The occurrence of endogenous 9-cis-retinol and the existence of specific dehydrogenase which participates in the catalysis of 9-cis-retinal suggest that all-trans-retinoi(d) isomerization to 9-cis-retinoi(d) occurs at the retinol level, analogous to all-trans-retinol isomerization to 11-cis-retinol in the visual cycle.

scholarly journals Retinoic acid-dependent activation of the polycystic kidney disease-1 (PKD1) promoter

2008 ◽  
Vol 295 (6) ◽  
pp. F1845-F1854 ◽  
Author(s):  
M. Rafiq Islam ◽  
Sanjeev Puri ◽  
Marianna Rodova ◽  
Brenda S. Magenheimer ◽  
Robin L. Maser ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Chromatin Immunoprecipitation ◽  
Mammalian Cells ◽  
Proximal Promoter ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Gc Box ◽  
Rna Knockdown ◽  
Interfering Rna

The retinoic acids all- trans retinoic acid (AT-RA) and 9- cis retinoic acid (9C-RA) and the retinoic acid receptors RAR and RXR significantly induce transcriptional activity from a 200-bp PKD1 proximal promoter in transfected mammalian cells. This PKD1 promoter region contains Ets, p53, and GC box motifs, but lacks a canonical RAR/RXR motif. Mutagenesis of the Ets sites did not affect RA induction. In contrast, GC box mutations completely blocked stimulation by AT-RA and by RXRβ or RARβ. Mithramycin A, which prevents Sp1 binding, significantly reduced basal promoter activity and suppressed upregulation by AT-RA and RXR. The 200-bp proximal promoter could not be induced by AT-RA in Drosophila SL2 cells, which lack Sp1, but could be activated in these cells transfected with exogenous Sp1. Small interfering RNA knockdown of Sp1 in mammalian cells completely blocked RXRβ upregulation of the promoter. These data indicate that induction of the PKD1 promoter by retinoic acid is mediated through Sp1 elements. RT-PCR showed that AT-RA treatment of HEK293T cells increased the levels of endogenous PKD1 RNA, and chromatin immunoprecipitation showed the presence of both RXR and Sp1 at the PKD1 proximal promoter. These results suggest that retinoids and their receptors may play a role in PKD1 gene regulation.

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