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Lawrence J. Singerman - One of the best experts on this subject based on the ideXlab platform.
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investigation of oral Fenretinide for treatment of geographic atrophy in age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2013Co-Authors: Nathan L. Mata, Jay Lichter, Roger Vogel, Lawrence J. SingermanAbstract:BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of Fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 μM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined Fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of Fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of Fenretinide in chronic dosing regimens warrant further study of Fenretinide in the treatment of geographic atrophy.
Reijo Laaksonen - One of the best experts on this subject based on the ideXlab platform.
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Fenretinide treatment accelerates atherosclerosis development in apoE-deficient mice in spite of beneficial metabolic effects.
British journal of pharmacology, 2019Co-Authors: Marco Busnelli, Stefano Manzini, Fabrizia Bonacina, S. Soldati, Silvia S. Barbieri, Patrizia Amadio, Leonardo Sandrini, Francesca Arnaboldi, Elena Donetti, Reijo LaaksonenAbstract:Background and purpose Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that Fenretinide may have an anti-atherosclerotic action. Experimental approach To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/w) Fenretinide. As a reference, wild-type (WT) mice were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses. Key results Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, Fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of Fenretinide-treated mice. Conclusions and implications We provide the first evidence that, despite beneficial metabolic effects, Fenretinide treatment may enhance the development of atherosclerosis.
Nathan L. Mata - One of the best experts on this subject based on the ideXlab platform.
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Effect of Fenretinide and its metabolites on DES1 activity.
2017Co-Authors: Eugenia Poliakov, Nathan L. Mata, William Samuel, Todd Duncan, Danielle B Gutierrez, Michael T RedmondAbstract:ARPE-19 cells were treated with Fenretinide, its metabolites, A1120 (all at 10 μM) or vehicle for 24 h, and endogenous C16 and C18 ceramides measured by LC/MS. Suppression of DES1 activity by Fenretinide and its metabolites is confirmed by the higher substrate/product (dihydroceramide/ceramide) ratio relative to the DMSO control. The presence of Fenretinide or 3-keto-HPR led to a greater accumulation of C16 and C18 dihydroceramide than did MPR or A1120. Lipids were extracted from one 100 mm Petri dish for each biological replicate and subjected to mass spectrometry analysis. Data plotted as means±standard deviation; n = 3.
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Inhibitory effects of Fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on Fenretinide molecular targets β-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide Δ4-desaturase 1.
'Public Library of Science (PLoS)', 2017Co-Authors: Eugenia Poliakov, Nathan L. Mata, William Samuel, Todd Duncan, Danielle B Gutierrez, Michael T RedmondAbstract:The therapeutic capacity of Fenretinide (N-[4-hydroxyphenyl] retinamide; 4-HPR) has been demonstrated for several conditions, including cancer, obesity, diabetes, and ocular disease. Yet, the mechanisms of action for its pleiotropic effects are still undefined. We hypothesized that investigation of two of the major physiological metabolites of Fenretinide, N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR), might begin to resolve the multifaceted effects of this synthetic retinoid. We analyzed the effects of Fenretinide, MPR, 3-keto-HPR, and the non-retinoid RBP4 ligand A1120, on the activity of known targets of Fenretinide, stearoyl-CoA desaturase 1 (SCD1) and dihydroceramide Δ4-desaturase 1 (DES1) in ARPE-19 cells, and purified recombinant mouse beta-carotene oxygenase 1 (BCO1) in vitro. Lipids and retinoids were extracted and quantified by liquid chromatography-mass spectrometry and reversed phase HPLC, respectively. The data demonstrate that while Fenretinide is an inhibitor of the activities of these three enzymes, that 3-keto-HPR is a more potent inhibitor of all three enzymes, potentially mediating most of the in vivo beneficial effects of Fenretinide. However, while MPR does not affect SCD1 and DES1 activity, it is a potent specific inhibitor of BCO1. We conclude that a deeper understanding of the mechanisms of action of Fenretinide and its metabolites provides new avenues for therapeutic specificity. For example, administration of 3-keto-HPR instead of Fenretinide may be preferential if inhibition of SCD1 or DES1 activity is the goal (cancer), while MPR may be better for BCO1 modulation (carotenoid metabolism). Continued investigation of Fenretinide metabolites in the context of Fenretinide's various therapeutic uses will begin to resolve the pleotropic nature of this compound
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Effect of Fenretinide and its metabolites on SCD expression and activity.
2017Co-Authors: Eugenia Poliakov, Nathan L. Mata, William Samuel, Todd Duncan, Danielle B Gutierrez, Michael T RedmondAbstract:A) SCD1 protein expression is decreased after treatment with Fenretinide, and its metabolite 3-keto-HPR. ARPE-19 cells were treated with the indicated concentration of Fenretinide, its metabolites, A1120, or vehicle for 24 h. Cell lysates were analyzed by Western blotting using mouse monoclonal antibody against SCD1 (upper panel) in comparison with immunoreactivity to α-tubulin which was employed as a loading control (lower panel) and densitometry for each lane was performed and analyzed by ImageJ to provide the SCD1/α-tubulin ratio for each lane. B) SCD1 protein activity is decreased after treatment with Fenretinide, and its metabolite 3-keto-HPR. ARPE-19 cells were treated with the indicated concentration of Fenretinide, its metabolites, A1120, or vehicle for 16 h, then incubated an additional 5 h in the presence of methyl D3-palmitic acid (50 μM) before harvesting. Free fatty acids present in lipid extracts were analyzed by LC/MS and SCD1 activity, measured by the conversion of methyl-D3 palmitic acid to methyl-D3 palmitoleic acid, was determined. Fenretinide and 3-keto-HPR are effective inhibitors of SCD1 activity, whereas MPR and A1120 have no inhibitory effect on SCD1 activity at all. Lipids were extracted from two 100 mm Petri dishes and combined for mass spectrometry analysis. Data plotted as means ± standard deviation; n = 3.
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Phenylretinamides and A1120 do not compete or compete poorly with 1 nM at-RA in RARbeta antagonist assay.
2017Co-Authors: Eugenia Poliakov, Nathan L. Mata, William Samuel, Todd Duncan, Danielle B Gutierrez, Michael T RedmondAbstract:Fenretinide is the only tested compound that appears to compete, exhibiting an IC50 = 10 μM. Fluorescence was measured at excitation (ex) 409 nm/emission (em) 460 and at ex 409nm/em 530 nm and the ratio was determined and plotted against a range of concentrations (10−5 to 10−9 M) of the tested compounds.
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investigation of oral Fenretinide for treatment of geographic atrophy in age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2013Co-Authors: Nathan L. Mata, Jay Lichter, Roger Vogel, Lawrence J. SingermanAbstract:BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol-binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of Fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of ≤ 1 μM (≤ 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined Fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of Fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of Fenretinide in chronic dosing regimens warrant further study of Fenretinide in the treatment of geographic atrophy.
Ji Zhang - One of the best experts on this subject based on the ideXlab platform.
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Fenretinide targets the side population in myeloma cell line nci h929 and potentiates the efficacy of antimyeloma with bortezomib and dexamethasone regimen
Leukemia Research, 2016Co-Authors: Wenqing Yan, Shuyan Liu, Ji Zhang, Jian HouAbstract:Side population (SP) cells, a subset of enriched tumor initiating cells, have been demonstrated to have stem cell-like properties in multiple myeloma (MM) by us as well as other previous studies. A lack of agents targeting tumor initiating cells, however, represents a challenge in the treatment of MM. Previously, Fenretinide, a well-tolerated vitamin A derivative, has been shown to exert effect on leukemic stem cells, but its actions against myeloma stem-like cells are still unknown. In this study, the effects of Fenretinide on myeloma stem-like cells characteristic was comprehensively examined in SP and non-SP (MP) cells of NCI-H929 cell sorted by flow cytometry-based on Hoechst 33342 stain. We find that Fenretinide is capable of eradicating MM SP and MP cells, but not normal bone marrow mononuclear cells (BMMCs) at physiologically achievable concentrations. Fenretinide alone exerted a selective cytotoxic effect on MM SP cells, as well as in combination with bortezomib and dexamethasone. In particular, SP cells were highly sensitive to Fenretinide, and in combination with bortezomib and dexamethasone in colony formation and apoptosis assays. Accordingly, the apparent Fenretinide-induced-apoptosis was linked to the rapid generation of reactive oxygen species (ROS). Therefore, we propose that Fenretinide is a potent agent that targets tumor initiating cells and may be a promising therapeutic agent in MM treatment.
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preferential involvement of both ros and ceramide in Fenretinide induced apoptosis of hl60 rather than nb4 and u937 cells
Biochemical and Biophysical Research Communications, 2011Co-Authors: Lulu Jiang, Ji Zhang, Xiaoling Pan, Ying Chen, Kankan WangAbstract:Leukemic cells responding to apoptosis-inducing drugs can be varied in terms of the mechanisms of action. Fenretinide, a synthetic retinoid, is worth of study as a promising candidate for apoptosis-based therapy of leukemia. Yet, it remains unclear whether this drug exerts the similar mechanisms on different leukemic cells. Here, we report a comparative analysis of Fenretinide-induced apoptosis in three acute myeloid leukemic (AML) cell lines including HL60, NB4 and U937. Through a series of antagonist assays, we revealed similarities and differences of mechanisms involved in these three cell lines. Antioxidant vitamin C completely abrogated Fenretinide-induced apoptosis in all cell lines, demonstrating that ROS is an essential and common mediator. However, the apoptotic effects of Fenretinide could be blocked by ceramide synthase inhibitor fumonisin B1 only in HL60 rather than the other two. Moreover, fumonisin B1 was unable to inhibit the generation of ROS in Fenretinide-treated HL60 cells, indicating that ROS may function as upstream stimulus of ceramide-mediated apoptosis. These comparative results strongly suggest that the apoptotic response induced by Fenretinide in HL60 involves both ROS and ceramide, whereas drug-induced apoptosis in NB4 and U937 requires ROS but is independent of ceramide. Differentiated modes of action exerting on AML may guide the use of this apoptosis-inducing drug, and hence advance our knowledge about the nature of cancer-specific responses to this drug.
Andrew S Holpuch - One of the best experts on this subject based on the ideXlab platform.
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evaluation of a mucoadhesive Fenretinide patch for local intraoral delivery a strategy to reintroduce Fenretinide for oral cancer chemoprevention
Carcinogenesis, 2012Co-Authors: Andrew S Holpuch, Kashappa Goud H Desai, Maynard P Phelps, Wei Chen, George Koutras, Byungdo B Han, Blake M Warner, Ping Pei, Garrett A Seghi, Meng TongAbstract:Systemic delivery of Fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of Fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest Fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in Fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1-TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1-UGT1A1) exhibited Fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels 5 μM) relative to blank-treated epithelium. All Fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4-CYP3A4) responsible for conversion of Fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed Fenretinide and 4-oxo-4-HPR's preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated Fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.
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mucoadhesive Fenretinide patches for site specific chemoprevention of oral cancer enhancement of oral mucosal permeation of Fenretinide by coincorporation of propylene glycol and menthol
Molecular Pharmaceutics, 2012Co-Authors: Xiao Wu, Kashappa Goud H Desai, Susan R Mallery, Andrew S Holpuch, Maynard P Phelps, Steven P SchwendemanAbstract:The objective of this study was to enhance oral mucosal permeation of Fenretinide by coincorporation of propylene glycol (PG) and menthol in Fenretinide/Eudragit RL PO mucoadhesive patches. Fenretinide is an extremely hydrophobic chemopreventive compound with poor tissue permeability. Coincorporation of 5–10 wt % PG (mean Js = 16–23 μg cm–2 h–1; 158–171 μg of Fenretinide/g of tissue) or 1–10 wt % PG + 5 wt % menthol (mean Js = 18–40 μg cm–2 h–1; 172–241 μg of Fenretinide/g of tissue) in Fenretinide/Eudragit RL PO patches led to significant ex vivo Fenretinide permeation enhancement (p < 0.001). Addition of PG above 2.5 wt % in the patch resulted in significant cellular swelling in the buccal mucosal tissues. These alterations were ameliorated by combining both enhancers and reducing PG level. After buccal administration of patches in rabbits, in vivo permeation of Fenretinide across the oral mucosa was greater (∼43 μg Fenretinide/g tissue) from patches that contained optimized permeation enhancer content ...