RESUMEN
It is widely reported that N-(4-hydroxyphenyl)-retinamide or fenretinide (4-HPR), which is a synthetic amide of all-trans-retinoic acid (ATRA), inhibits in vitro several types of tumors, including cancer cell lines resistant to ATRA, at 1-10 µM concentrations. Additionally, studies in rats and mice have confirmed the potent anticancer effects of 4-HPR, without evidencing hemolytic toxicity, thus demonstrating its suitability for the development of a new chemo-preventive agent. To this end, the accurate determination of 4-HPR levels in tissues is essential for its pre-clinical training, and for the correct determination of 4-HPR and its metabolites by chromatography, N-(4-ethoxyphenyl)-retinamide (4-EPR) has been suggested as an indispensable internal standard. Unfortunately, only a consultable old patent reports the synthesis of 4-EPR, starting from dangerous and high-cost reagents and using long and tedious purification procedures. To the best of our knowledge, no article existed so far describing the specific synthesis of 4-EPR. Only two vendors worldwide supply 4-ERP, and its characterization was incomplete. Here, a scalable, operator-friendly, and one-step procedure to synthetize highly pure 4-EPR without purification work-up and in quantitative yield is reported. Additionally, a complete characterization of 4-EPR using all possible analytical techniques has been provided.
Asunto(s)
Antineoplásicos , Fenretinida , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Fenretinida/metabolismo , Fenretinida/farmacología , Ratones , Ratas , Tretinoina/análogos & derivados , Tretinoina/farmacologíaRESUMEN
Retinoids are widely used in diseases spanning from dermatological lesions to cancer, but exhibit severe adverse effects. A novel all-trans-Retinoic Acid (atRA)-spermine conjugate (termed RASP) has shown previously optimal in vitro and in vivo anti-inflammatory and anticancer efficacy, with undetectable teratogenic and toxic side-effects. To get insights, we treated HaCaT cells which resemble human epidermis with IC50 concentration of RASP and analyzed their miRNA expression profile. Gene ontology analysis of their predicted targets indicated dynamic networks involved in cell proliferation, signal transduction and apoptosis. Furthermore, DNA microarrays analysis verified that RASP affects the expression of the same categories of genes. A protein-protein interaction map produced using the most significant common genes, revealed hub genes of nodal functions. We conclude that RASP is a synthetic retinoid derivative with improved properties, which possess the beneficial effects of retinoids without exhibiting side-effects and with potential beneficial effects against skin diseases including skin cancer.
Asunto(s)
Queratinocitos/efectos de los fármacos , MicroARNs/metabolismo , Espermina/análogos & derivados , Transcriptoma , Tretinoina/análogos & derivados , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Relación Dosis-Respuesta a Droga , Redes Reguladoras de Genes , Células HaCaT , Humanos , Concentración 50 Inhibidora , Queratinocitos/metabolismo , Queratinocitos/patología , MicroARNs/genética , Mapas de Interacción de Proteínas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Espermina/farmacología , Espermina/toxicidad , Tretinoina/farmacología , Tretinoina/toxicidadRESUMEN
Small-molecule drugs inhibiting BK polyomavirus (BKPyV) represent a significant unmet clinical need in view of polyomavirus-associated nephropathy or hemorrhagic cystitis, which complicate 5% to 25% of kidney and hematopoietic cell transplantations. We characterized the inhibitory activity of acitretin on BKPyV replication in primary human renal proximal tubular epithelial cells (RPTECs). Effective inhibitory concentrations of 50% (EC50) and 90% (EC90) were determined in dilution series measuring BKPyV loads, transcripts, and protein expression, using cell proliferation, metabolic activity, and viability to estimate cytotoxic concentrations and selectivity indices (SI). The acitretin EC50 and EC90 in RPTECs were 0.64 (SI50, 250) and 3.25 µM (SI90, 49.2), respectively. Acitretin effectively inhibited BKPyV replication until 72 h postinfection when added 24 h before infection until 12 h after infection, but decreased to <50% at later time points. Acitretin did not interfere with nuclear delivery of BKPyV genomes, but it decreased large T-antigen transcription and protein expression. Acitretin did not inhibit the initial round of BKPyV replication following transfection of full-length viral genomes, but it affected subsequent rounds of reinfection. Acitretin also inhibited BKPyV replication in human urothelial cells and in Vero cells, but not in COS-7 cells constitutively expressing Simian virus 40 (SV40) large T antigen. Retinoic acid agonists (all-trans retinoic acid, 9-cis retinoic acid [9-cis-RA], 13-cis-RA, bexarotene, and tamibarotene) and the RAR/RXR antagonist RO41-5253 also inhibited BKPyV replication, pointing to an as-yet-undefined mechanism. IMPORTANCE Acitretin selectively inhibits BKPyV replication in primary human cell culture models of nephropathy and hemorrhagic cystitis. Since acitretin is an approved drug in clinical use reaching BKPyV-inhibiting concentrations in systemically treated patients, further studies are warranted to provide data for clinical repurposing of retinoids for treatment and prevention of replicative BKPyV-diseases.
Asunto(s)
Acitretina/farmacología , Antivirales/farmacología , Virus BK/crecimiento & desarrollo , Retinoides/farmacología , Tretinoina/farmacología , Replicación Viral/efectos de los fármacos , Animales , Antígenos Virales de Tumores/biosíntesis , Antígenos Virales de Tumores/genética , Células COS , Línea Celular , Chlorocebus aethiops , Cistitis/tratamiento farmacológico , Cistitis/virología , Genoma Viral/genética , Células HEK293 , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/virología , Pruebas de Sensibilidad Microbiana , Infecciones por Polyomavirus/tratamiento farmacológico , Tretinoina/análogos & derivados , Infecciones Tumorales por Virus/tratamiento farmacológico , Células VeroRESUMEN
All-trans-retinoic acid (ATRA) is effective for preventing cancer and treating skin diseases and acute promyelocytic leukaemia (APL). These pharmacological effects of ATRA are mainly mediated by retinoid X receptors (RXRs) and retinoic acid receptors (RARs). This article provides a comprehensive overview of the clinical progress on and the molecular mechanisms of ATRA in the treatment of APL. ATRA can promote the transcriptional activation of differentiation-related genes and regulate autophagy by inhibiting mTOR, which results in anti-APL effects. In detail, the structures, pharmacological effects, and clinical studies of 68 types of ATRA analogues are described. These compounds have excellent antitumour therapeutic potential and could be used as lead compounds for further development and research.
Asunto(s)
Antineoplásicos/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Tretinoina/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Serina-Treonina Quinasas TOR/metabolismo , Tretinoina/análogos & derivados , Tretinoina/químicaRESUMEN
Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-ß,ß-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-ß,ß-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-ß,ß-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named "Vitamin A5/X".
Asunto(s)
Receptores X Retinoide/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tretinoina/análogos & derivados , Vitaminas/farmacología , Animales , Células Cultivadas , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Oligodendroglía/efectos de los fármacos , Provitaminas/análisis , Provitaminas/síntesis química , Provitaminas/farmacología , Tretinoina/farmacología , Vitamina A/análogos & derivados , Vitamina A/metabolismo , Vitaminas/análisis , Vitaminas/síntesis químicaRESUMEN
The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.
Asunto(s)
Piel/efectos de los fármacos , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/citología , Piel/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Tretinoina/uso terapéuticoRESUMEN
FMS-like tyrosine kinase 3 (FLT3) mutation is strongly associated with poor prognosis in acute myeloid leukemia (AML). Though many FLT3 inhibitors have been developed for clinical application with 34%-56% complete remission rate, patients would develop resistance sooner or later after initial response to tyrosine kinase inhibitors (TKIs), such as gilteritinib. And increasing studies have shown that several resistance related mutations of FLT3 emerged during the AML progression. Thus, further investigation is warranted for these FLT3mut AML patients to achieve a better treatment outcome. 4-Hydroxyphenyl retinamide (4-HPR) has been investigated extensively in animal models and clinical trials as an anticancer/chemopreventive agent and is currently used for protection against cancer development/recurrence, with minimal side effects. In this study, we performed gene-set enrichment analysis and found that down-regulated genes induced by 4-HPR were associated with FLT3-ITD gene sets. CD34+ AML stem/progenitor cells separated from 32 AML samples were treated with 4-HPR. Correlation analysis showed that AML cells with FLT3-ITD genetic alteration were more sensitive to 4-HPR treatment than those without FLT3-ITD. Next, we treated 22 primary AML cells with 4-HPR and found that 4-HPR was more toxic to AML cells with FLT3-ITD. These results indicated that 4-HPR was preferentially cytotoxic to all FLT3-ITD AML+ cells irrespective of stem/progenitor cells or blast cells. 4-HPR-induced reactive oxygen species (ROS) production and NF-κB inhibition might be the reason of 4-HPR selectivity on FLT3 mutated AML cells.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Tretinoina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/genética , Compuestos de Anilina/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación/genética , FN-kappa B/genética , Pirazinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Tretinoina/farmacologíaRESUMEN
Important key players in the regulatory machinery within the cells are nuclear retinoid X receptors (RXRs), which compose heterodimers in company with several diverse nuclear receptors, playing a role as ligand inducible transcription factors. In general, nuclear receptors are ligand-activated, transcription-modulating proteins affecting transcriptional responses in target genes. RXR molecules forming permissive heterodimers with disparate nuclear receptors comprise peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstan receptor (CAR). Retinoid receptors (RARs) and thyroid hormone receptors (TRs) may form conditional heterodimers, and dihydroxyvitamin D3 receptor (VDR) is believed to form nonpermissive heterodimer. Thus, RXRs are the important molecules that are involved in control of many cellular functions in biological processes and diseases, including cancer or diabetes. This article summarizes both naturally occurring and synthetic ligands for nuclear retinoid X receptors and describes, predominantly in mammals, their role in molecular mechanisms within the cells. A focus is also on triorganotin compounds, which are high affinity RXR ligands, and finally, we present an outlook on human microbiota as a potential source of RXR activators. Nevertheless, new synthetic rexinoids with better retinoid X receptor activity and lesser side effects are highly required.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/fisiología , Receptores X Retinoide/fisiología , Animales , Humanos , Ligandos , Microbiota , Compuestos Orgánicos de Estaño/farmacología , Receptores X Retinoide/agonistas , Tretinoina/análogos & derivados , Tretinoina/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide due to its high rate of recurrence, in part because of cancer stem cell (CSC)-dependent "field cancerization". Recently, we identified that the oncogene v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) marked CSC-like subpopulations in heterogeneous HCC and served as a therapeutic target and prognostic marker for HCC. In this study, we explored the molecular basis of upregulated MYCN gene expression in HCC cells. Liquid chromatograph time-of-flight mass spectrometry-based metabolome analysis demonstrated that the content of unsaturated fatty acids was increased in MYCN high expression (MYCNhigh) CSC-like HCC cells. Inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against stearoyl-CoA desaturase-1 (SCD1) suppressed cell proliferation as well as MYCN gene expression in MYCNhigh HCC cells, grown as both monolayer and spheres. Further mechanistic study using RNA-seq based transcriptome analysis revealed that endoplasmic reticulum (ER) stress related signaling networks such as endocannabinoid cancer inhibition pathway were under the control of SCD1 in MYCNhigh HCC cells. Furthermore, the expression of ER stress-inducible transcription suppressor cyclic AMP-dependent transcription factor (ATF3) was downregulated in MYCNhigh CSC-like HCC cells and CSC-rich spheroids, which was upregulated by inhibition of lipid desaturation or treatment with acyclic retinoid (ACR). Lipid profiling using NMR spectroscopy revealed that the ACR dramatically reduced the content of unsaturated fatty acids in HCC cells. The chemical inducer of ER stress inhibited MYCN gene expression, while the chemical inhibitor of ER stress or knockdown of ATF3 gene expression partially rescued the suppression of MYCN gene expression by ACR in MYCNhigh HCC cells. These data suggested that lipid desaturation-mediated ER stress signaling regulates MYCN gene expression in HCC cells and serves as a promising therapeutic target for the treatment and prevention of HCC.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Estrés del Retículo Endoplásmico/genética , Ácidos Grasos Insaturados/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cromatografía Liquida , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos Insaturados/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Metaboloma , Proteína Proto-Oncogénica N-Myc/genética , Células Madre Neoplásicas/metabolismo , Organoides/efectos de los fármacos , Organoides/metabolismo , ARN Interferente Pequeño , RNA-Seq , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Tretinoina/farmacologíaRESUMEN
The rapidly accelerated fibrosarcoma (Raf) kinase is canonically activated by growth factors that regulate multiple cellular processes. In this kinase cascade Raf activation ultimately results in extracellular regulated kinase 1/2 (Erk1/2) activation, which requires Ras binding to the Ras binding domain (RBD) of Raf. We recently reported that all-trans retinoic acid (atRA) rapidly (within minutes) activates Erk1/2 to modulate cell cycle progression in stem cells, which is mediated by cellular retinoic acid binding protein 1 (Crabp1). But how atRA-bound Crabp1 regulated Erk1/2 activity remained unclear. We now report Raf kinase as the direct target of atRA-Crabp1. Molecularly, Crabp1 acts as a novel atRA-inducible scaffold protein for Raf/Mek/Erk in cells without growth factor stimulation. However, Crabp1 can also compete with Ras for direct interaction with the RBD of Raf, thereby negatively modulating growth factor-stimulated Raf activation, which can be enhanced by atRA binding to Crabp1. NMR heteronuclear single quantum coherence (HSQC) analyses reveal the 6-strand ß-sheet face of Crabp1 as its Raf-interaction surface. We identify a new atRA-mimicking and Crabp1-selective compound, C3, that can also elicit such an activity. This study uncovers a new signal crosstalk between endocrine (atRA-Crabp1) and growth factor (Ras-Raf) pathways, providing evidence for atRA-Crabp1 as a novel modulator of cell growth. The study also suggests a new therapeutic strategy by employing Crabp1-selective compounds to dampen growth factor stimulation while circumventing RAR-mediated retinoid toxicity.
Asunto(s)
Receptores de Ácido Retinoico/metabolismo , Transducción de Señal , Quinasas raf/metabolismo , Animales , Sitios de Unión , Células Cultivadas , Ratones , Unión Proteica , Conformación Proteica en Lámina beta , Receptores de Ácido Retinoico/química , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Quinasas raf/químicaRESUMEN
BACKGROUND/AIM: Despite intensive chemotherapy, the survival rates for high-risk neuroblastoma, most of which have MYCN amplification, remain low. Overexpression of N-myc oncoprotein promotes expression of cancer-associated properties. We recently found that combination of all-trans retinoic acid (ATRA) with the ß1-integrin-activating peptide TNIIIA2 attenuated cancer-associated properties of neuroblastoma cells through N-Myc degradation. However, ATRA has serious side-effects and there are concerns about late adverse effects. The aim of this study was to examine the effects of the combination of acyclic retinoid (ACR) with TNIIIA2 on neuroblastoma. MATERIALS AND METHODS: The effects of ACR and TNIIIA2 were examined by neuroblastoma cell proliferation and survival assays as well as by using a neuroblastoma xenograft model. The levels of N-Myc and cancer-associated malignant properties were assayed by western blot and colony formation assay, respectively. RESULTS: Combining ACR, which is clinically safe, with TNIIIA2 induced proteasomal degradation of N-Myc and reduction of neuroblastoma cell malignant properties. An in vivo experiment showed therapeutic potential. CONCLUSION: ACR-TNIIIA2 combination treatment may be efficacious and clinical safe chemotherapy for high-risk neuroblastoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/tratamiento farmacológico , Péptidos/uso terapéutico , Tenascina/uso terapéutico , Tretinoina/análogos & derivados , Animales , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Péptidos/farmacología , Fenotipo , Tenascina/farmacología , Tretinoina/farmacología , Tretinoina/uso terapéutico , Carga Tumoral/efectos de los fármacosRESUMEN
Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores Farmacológicos/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Isotretinoína/farmacología , Neuroblastoma/genética , Tretinoina/análogos & derivados , Tretinoina/farmacología , Adolescente , Bexaroteno/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Niño , Preescolar , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Resistencia a Antineoplásicos/genética , Femenino , Fenretinida/farmacología , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Neoplasias del Sistema Nervioso/genética , Neoplasias del Sistema Nervioso/metabolismo , Neoplasias del Sistema Nervioso/patología , Neoplasias del Sistema Nervioso/cirugía , Neuroblastoma/metabolismo , Neuroblastoma/patología , Neuroblastoma/cirugía , Adhesión en Parafina , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismo , Fijación del Tejido , Adulto JovenAsunto(s)
Antineoplásicos/toxicidad , Trióxido de Arsénico/toxicidad , Quimioterapia Combinada/efectos adversos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Mioclonía/inducido químicamente , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Intoxicación por Arsénico/diagnóstico , Trióxido de Arsénico/administración & dosificación , Trióxido de Arsénico/uso terapéutico , Quimioterapia Combinada/métodos , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/uso terapéutico , Leucemia Promielocítica Aguda/patología , Inducción de Remisión , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Inhibidores de Topoisomerasa II/administración & dosificación , Inhibidores de Topoisomerasa II/uso terapéutico , Resultado del Tratamiento , Tretinoina/administración & dosificación , Tretinoina/análogos & derivados , Tretinoina/uso terapéutico , Privación de TratamientoRESUMEN
BACKGROUND: Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes. METHODS: Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs). RESULTS: OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment. CONCLUSIONS: ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.
Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Transformación Celular Neoplásica/inducido químicamente , Dietilnitrosamina/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/prevención & control , Sustancias Protectoras/farmacología , Tretinoina/análogos & derivados , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentales , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas OLETF , Tretinoina/farmacologíaRESUMEN
Objective: To explore the effects of N-(4-hydroxyphenyl) retinamide (4HPR), 4HPR liposome (4HPR-L), and 4HPR lipid microbubble (4HPR-LM) combined with ultrasound on proliferation, apoptosis, and cell cycle of human keloid fibroblasts (Fbs). Methods: (1) 4HPR-L and 4HPR-LM were prepared by hydration ultrasonic method. The appearance morphology, particle size distribution, Zeta potential, loading drug concentration, encapsulation efficiency, and drug loading rate of 4HPR-L were investigated by high performance liquid chromatography, dynamic light scattering, and transmission electron microscope. (2) Human keloid Fbs were cultured and divided into 13 groups by random number table (the same grouping method below), with 6 wells in each group. Cells in control group were given no treatment, while cells in 12 ultrasound groups including 0.5 W 30 s group, 0.5 W 60 s group, 0.5 W 120 s group, 0.7 W 30 s group, 0.7 W 60 s group, 0.7 W 120 s group, 1.0 W 30 s group, 1.0 W 60 s group, 1.0 W 120 s group, 1.5 W 30 s group, 1.5 W 60 s group, and 1.5 W 120 s group were treated by ultrasound with corresponding parameters. The cells viability was measured by a microplate reader after 24 hours of routine culture. Another batch of human keloid Fbs were divided into 5 groups, with 6 wells in each group. Cells in control group were given no treatment, while cells in 1, 10, 20, and 50 µg/mL blank lipid microbubble groups were treated with blank lipid microbubbles in corresponding mass concentration. The cells viability was measured as before after 24 hours of routine culture. Another batch of human keloid Fbs were divided into 6 groups, with 12 wells in each group. Cells in control group were given no treatment, while cells in 1, 10, 20, 50, and 100 µg/mL 4HPR-L groups were added with 4HPR-L carrying corresponding mass concentration of 4HPR. The cells viability in 6 wells of each group was detected after 24 and 48 hours of routine culture, respectively. Another batch of human keloid Fbs were divided into 4 groups, with 6 wells in each group. Cells in control group were given no treatment, while cells in 4HPR, 4HPR-L, and 4HPR-LM+ ultrasound groups were treated with 4HPR, 4HPR-L, and 4HPR-LM (all the mass concentration of 4HPR was 20 µg/mL), respectively, and cells in 4HPR-LM+ ultrasound group were given 0.5 W 60 s ultrasound treatment immediately after drug administration. The cells viability was measured as before after 24 hours of routine culture. (3) Another batch of human keloid Fbs were divided into control group, 4HPR group, 4HPR-L group and 4HPR-LM+ ultrasound group, with 3 wells in each group, and the cells in each group were treated as before. Apoptosis of the cells was detected by flow cytometer after 24 hours of routine culture. (4) Another batch of human keloid Fbs were grouped and treated as in (3), and then the cell cycle distribution was detected by flow cytometer after 24 hours of routine culture. Data were processed with one-way analysis of variance and t test. Results: (1) 4HPR-L particles had a spherical or spheroidal structure and were uniform in size, with particle size of (100.1±1.3) nm and Zeta potential of (-34.3±2.3) mV. The mass concentration of 4HPR in 4HPR-L solution was about 1 400 µg/mL, with the encapsulation efficiency of (95.8±1.2)% and drug loading rate of (8.3±0.4)%. (2) The viability of cells in the 12 ultrasound groups was higher than 93.0%, and the viability of cells in 1, 10, 20, and 50 µg/mL blank lipid microbubble groups was higher than 95.0%. The viability of cells in 1 µg/mL 4HPR-L group at administration hour 24 was similar to that at 48 (t=0.393, P>0.05). The viability of cells in 10, 20, 50, and 100 µg/mL 4HPR-L groups at administration hour 24 was significantly higher than that at administration hour 48 (t=44.593, 22.961, 32.224, 35.337, P<0.01). The viability of cells in 4HPR group, 4HPR-L group, and 4HPR-LM+ ultrasound group was (47.3±0.7)%, (42.3±1.7)%, and (38.6±0.8)%, respectively. The viability of cells in 4HPR group was significantly higher than that in 4HPR-L group and 4HPR-LM+ ultrasound group (t=4.551, 15.895, P<0.05 or P<0.01). The viability of cells in 4HPR-L group was significantly higher than that in 4HPR-LM+ ultrasound group (t=-3.360, P<0.05). (3) The percentages of total apoptotic cells in 4HPR group, 4HPR-L group, and 4HPR-LM+ ultrasound group were (32.8±2.4)%, (42.5±2.4)%, and (58.5±6.3)%, respectively, which were significantly higher than the percentage of control group [(14.9±1.6)%, t=8.748, 13.637, 9.500, P<0.01]. The percentages of total apoptotic cells in 4HPR-L group and 4HPR-LM+ ultrasound group were significantly higher than the percentage in 4HPR group (t=4.049, 5.393, P<0.05 or P<0.01), and the percentage of total apoptotic cells in 4HPR-LM+ ultrasound group was significantly higher than that in 4HPR-L group (t=3.371, P<0.01). (4) The percentage of G2/M phase cells in 4HPR group was higher than that in control group, but there was no statistically significant difference (t=2.107, P>0.05). The percentage of G2/M phase cells in 4HPR-L group was significantly higher than that in 4HPR group or control group (t=18.169, 30.026, P<0.01). The percentage of G2/M phase cells in 4HPR-LM+ ultrasound group was significantly higher than that in 4HPR-L group, 4HPR group, and control group (t=4.932, 25.854, 66.231, P<0.01). Conclusions: 4HPR can inhibit proliferation, induce apoptosis, and arrest G2/M phase of human keloid Fbs, and the effects of 4HPR-LM combined with ultrasound are better than those of 4HPR-L and free 4HPR.
Asunto(s)
Queloide , Lípidos , Microburbujas , Apoptosis , Proliferación Celular , Humanos , Tretinoina/análogos & derivadosRESUMEN
The identity of the endogenous RXR ligand has not been conclusively determined, even though several compounds of natural origin, including retinoids and fatty acids, have been postulated to fulfill this role. Filling this gap, 9-cis-13,14-dihydroretinoic acid (9CDHRA) was identified as an endogenous RXR ligand in mice. This review examines the physiological relevance of various potential endogenous RXR ligands, especially 9CDHRA. The elusive steps in the metabolic synthesis of 9CDHRA, as well as the nutritional/nutrimetabolic origin of 9CDHRA, are also explored, along with the suitability of the ligand to be the representative member of a novel vitamin A class (vitamin A5).
Asunto(s)
Receptores X Retinoide/metabolismo , Proteínas de Unión al Retinol/metabolismo , Vitamina A/metabolismo , Animales , Humanos , Ligandos , Receptores de Ácido Retinoico/metabolismo , Retinoides/metabolismo , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Vitamina A/análogos & derivados , Vitaminas/metabolismoRESUMEN
Viaminate is a derivative of retinoic acid (tretinoin) used in the treatment of severe acne and other disorders of keratinization. Liver dysfunction due to viaminate therapy has not been well described and there have been no reported deaths due to viaminate-induced hepatotoxicity. Herein, we report the case of a woman who underwent treatment at the hospital for 38 days and died of hepatic failure after taking viaminate for more than 2 months. This case provides further insight into viaminate-induced hepatotoxicity.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Tretinoina/análogos & derivados , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Resultado Fatal , Femenino , Humanos , Tretinoina/administración & dosificación , Tretinoina/efectos adversosRESUMEN
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
Asunto(s)
Antineoplásicos/administración & dosificación , Bexaroteno/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Mucosa Intestinal/metabolismo , Sistema Linfático/metabolismo , Profármacos/administración & dosificación , Tretinoina/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Bexaroteno/análogos & derivados , Bexaroteno/farmacocinética , Esterificación , Ganglios Linfáticos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Profármacos/química , Profármacos/farmacocinética , Ratas Sprague-Dawley , Distribución Tisular , Tretinoina/análogos & derivados , Tretinoina/farmacocinéticaRESUMEN
Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix-loop-helix-zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/ß-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM- cells. In a long-term (>10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/prevención & control , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hepáticas/prevención & control , Proteína Proto-Oncogénica N-Myc/biosíntesis , Células Madre Neoplásicas/metabolismo , Tretinoina/análogos & derivados , Vía de Señalización Wnt/efectos de los fármacos , Animales , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Molécula de Adhesión Celular Epitelial/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia , Células Madre Neoplásicas/patología , Pronóstico , Tretinoina/farmacologíaRESUMEN
VNLG-152 is a novel retinamide (NR) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E (eIF4E) translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration-resistant prostate cancer (CRPC) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg-1 bw, respectively (P < 0.0001), vs. vehicle with no host toxicity. Strikingly, the expression of full-length androgen receptor (f-AR)/androgen receptor splice variant-7 (AR-V7), mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2), phosphorylated eIF4E and their associated target proteins, including prostate-specific antigen, cyclin D1 and Bcl-2, were strongly decreased in VNLG-152-treated tumors signifying inhibition of f-AR/AR-V7 and MNK-eIF4E signaling in VNLG-152-treated CWR22Rv1 tumors as observed in vitro. VNLG-152 also suppressed the epithelial to mesenchymal transition in CWR22Rv1 tumors as evidenced by repression of N-cadherin, ß-catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases (MMP-2 and MMP-9) with upsurge in E-cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justify its further development towards clinical trials.