Retinoic Acid Drugs Research Articles

A novel retinoic acid drug, EYE-502, inhibits choroidal neovascularization by targeting endothelial cells and pericytes

Choroidal neovascularization (CNV) occurs in neovascular age-related macular degeneration (AMD) and often leads to permanent visual impairment. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is the gold standard for the treatment of CNV. However, anti-VEGF treatment did not always cause vision improvement and sometimes had detrimental effects on normal retinal tissues. Herein, we identified a novel retinoic acid drug, EYE-502, which had great therapeutic effects on CNV. Administration of EYE-502 could inhibit VEGF-induced dysfunction of endothelial cells (ECs) and reduce platelet-derived growth factor (PDGF)-induced recruitment of pericytes to ECs in vitro. Administration of EYE-502 could reduce the area of choroidal sprouting and laser-induced CNV, exhibiting similar anti-angiogenic effects as aflibercept. Moreover, administration of EYE-502 could reduce pericyte coverage in the sprouting vessels and choroidal neovascularization. Mechanistically, EYE-502 primarily bound to retinoic acid receptors (RARs) and exerted the anti-angiogenic effects by targeting ECs and pericytes via affecting the activation of Wnt/β-catenin and PDGF/PDGFR/PI3K/Akt signaling. Taken together, this study reports a novel retinoic acid drug, EYE-502, which can exert the anti-angiogenic effects by simultaneous targeting of ECs and pericytes.

Retinoic acid preparations in the complex treatment of acute promyelocytic leukemia

The results of the treatment of 11 patients with acute promyelocyte leukosis using the retinoic acid drugs (ATRA, 13-cis-retinoic acid) are presented. Total remission was achieved in 6 out of 9 patients within 2239 days of treatment: in 2 patients on ATRA monotherapy and in 4 patients in combination with polychemotherapy. Normalization of hemostasis indices with tendency to hypercoagulation is noted during the first week. Cupping of hemorrhages took place within 1430 days of treatment. High incidence (67%) of the retinoic acid syndrome is noted. It is connected with the initial hyperleukocytosis and not always timely prescription of polychemotherapy. Less dramatic nature of the disease course, fast cupping of hemorrhages, absence of the bone marrow aplasia phase, decrease of demand in transfusional provision were observed in using ATRA.

Investigation on the Binding and Conformational Change of All-trans-Retinoic Acid with Peptidyl Prolyl cis/trans Isomerase Pin1 Using Spectroscopic and Computational Techniques

Binding and conformational change of all-trans-retinoic acid (ATRA) with peptidyl prolyl cis/trans isomerase Pin1 were investigated systematically by spectroscopic and computational techniques under experimentally optimized physiological conditions. The intrinsic fluorescence of Pin1 was quenched through a static quenching mechanism in the presence of ATRA with binding constants on the order of 105 mol/L. Thermodynamic parameters (ΔH = 15.76 kJ/mol and ΔS = 158.36 J/mol·K at 293 K) and computational results illustrated that the hydrophobic interactions played a significant role in the binding process of ATRA to Pin1, but electrostatic forces, weak van der Waals, and hydrogen bonds cannot be ignored. Circular dichroism, fluorescence spectra, and computational simulations revealed that ATRA interacted with residues Lys63 and Arg69 of Pin1 to affect its conformational changes. Molecular dynamic simulation, principal component analysis, and free energy landscape monitored the dynamical conformational characteristics of ATRA binding to Pin1. All in all, the present research might provide a reference for the development and design of retinoic acid drugs that inhibit the activity of Pin1.

Mechanism of anti-scarring effect of retinoic acid drug delivery system in glaucoma filtration surgery in rabbits

Objective To investigate the mechanism of postoperative anti-scarring effect of retinoic acid (RA) drug delivery system (RADDS) on a rabbit model of glaucoma filtration surgery.Methods Glaucoma filtration surgery was performed on both eyes of 25 New Zealand white rabbits.The left eyes received RADDS (RA + PLGA),15 right eyes only randomly received drug delivery system (PLGA),and remaining 10 right eyes served as null vehicle (NV).The rabbits were killed on the day 7,14,30,60and 90 after the surgery.Both eyes were enucleated and tissue sections were immunohistochemically stained for proliferating cell nuclear antigen (PCNA) and transforming growth factor-52 (TGF-β2) of fibroblasts in surgery sites of rabbits' eyes.Semi-quantification of TGF-β2 mRNA was performed using reverse transcription-polymerase chain reaction (RT-PCR).Results The RA drug delivery system reduced fibroblast activity,with a significant reduction in the number and expression of PCNA in fibroblasts (P ＜ 0.01).RADDS treatment could significantly reduce the expression of TGF-β2 protein and mRNA (P ＜0.01).Conclusion The effect of postoperative anti-scarring of RA drug delivery system was mediated by inhibiting proliferation of fibroblasts and altering the expression of TGF-β2. Key words: Retinoic acid ; Glaucoma filtration surgery; Scarring; Proliferating cell nuclear antigen; Transforming growth factor-β

Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells

Retinoids display anti-tumour activity on various cancer cells and therefore have been used as important therapeutic agents. However, adverse side effects and RA (retinoic acid) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report in the present paper the identification of a natural marine product that activates RARs (RA receptors) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide was uncovered as a novel RAR agonist by inducing co-activator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unravelled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current RA drugs.

Retinoic Acid Induction of CD38 Antigen Expression on Normal and Leukemic Human Myeloid Cells: Relationship with Cell Differentiation

Differentiation in the hematopoietic system involves, among other changes, altered expression of antigens, including the CD34 and CD38 surface antigens. In normal hematopoiesis, the most immature stem cells have the CD34+CD34 m phenotype. In acute myeloid leukemia (AML), although blasts from most patients are CD38+, some are CD38 m. AML blasts are blocked at early stages of differentiation; in some leukemic cells this block can be overcome by a variety of agents, including retinoids, that induce maturation into macrophages and granulocytes both in vitro and in vivo. Retinoids can also induce CD38 expression. In the present study, we investigated the relationship between induction of CD38 expression and induction of myeloid differentiation by retinoic acid (RA) in normal and leukemic human hematopoietic cells. In the promyelocytic (PML) CD34 m cell lines, HL60 and CB-1, as well as in normal CD34+CD34 m hematopietic progenitor cells RA induced both CD38 expression as well as morphological and functional myeloid differentiation that resulted in loss of self-renewal. In contrast, in the myeloblastic CD34+ leukemic cell lines, ML-1 and KG-1a, as well as in primary cultures of cells derived from CD34+-AML (M 0 and M 1 ) patients, RA caused an increase in CD38+ that was not associated with significant differentiation. Yet, long exposure of ML-1, but not KG-1, cells to RA resulted in loss of self-renewal. The results suggest that while in normal hematopoietic cells and in PML CD34 m cells induction of CD38 antigen expression by RA results in terminal differentiation along the myeloid lineage, in early myeloblastic leukemic CD34+ cells, induction of CD38 and differentiation are not functionally related. Since, several lines of evidence suggest that the CD38 m cells are the targets of leukemic transformation, transition of these cells into CD38+ phenotype by RA or other drugs may have therapeutic effect, either alone or in conjunction with cytotoxic drugs, regardless the ability of the cells to undergo differentiation.