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Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. Understanding the molecular profile of such tumors allowed the development of specific targeted therapies toward GBM, with a major role attributed to tyrosine kinase receptor inhibitors and immune checkpoint inhibitors. Targeted therapeutics are drugs that work by specific binding to GBM-specific or overexpressed markers on the tumor cellular surface and therefore contain a recognition moiety linked to a cytotoxic agent, which produces an antiproliferative effect. In this review, we have summarized the available information on the targeted therapeutics used in clinical trials of GBM and summarized current obstacles and advances in targeted therapy concerning specific targets present in GBM tumor cells, outlined efficacy endpoints for major classes of investigational drugs, and discussed promising strategies towards an increase in drug efficacy in GBM.
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Rationale: The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness. Methods: A lipidomics approach was employed to assess the endocannabinoidome in the brains of Dominant (Dom) and Submissive (Sub) mice. The endocannabinoid showing the greatest difference in concentration in the brain between the groups, docosatetraenoyl ethanolamine (DEA), was synthesized, and its effects on the physiological and behavioral responses of Dom and Sub mice were evaluated. mRNA expression of the endocannabinoid receptors and enzymes involved in PUFA biosynthesis was assessed using qRT-PCR. Results: Targeted LC/MS analysis revealed that long-chain polyunsaturated ethanolamides including arachidonoyl ethanolamide (AEA), DEA, docosatrienoyl ethanolamide (DTEA), eicosatrienoyl ethanolamide (ETEA), eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) were higher in the Sub compared with the Dom mice. Untargeted LC/MS analysis showed that the parent fatty acids, docosatetraenoic (DA) and eicosapentaenoic (EPA), were higher in Sub vs. Dom. Gene expression analysis revealed increased mRNA expression of genes encoding the desaturase FADS2 and the elongase ELOVL5 in Sub mice compared with Dom mice. Acute DEA administration at the dose of 15 mg/kg produced antinociceptive and locomotion-inducing effects in Sub mice, but not in Dom mice. Subchronic treatment with DEA at the dose of 5 mg/kg augmented dominant behavior in wild-type ICR and Dom mice but not in Sub mice. Conclusion: This study suggests that the endocannabinoid system may play a role in the regulation of dominance and submissiveness, functional elements of social behavior and personality. While currently we have only scratched the surface, understanding the role of the endocannabinoid system in personality may help in revealing the mechanisms underlying the etiopathology of psychiatric disorders.
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There is growing interest in non-psychoactive phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), and cannabichromene, as potential leads for novel therapeutic agents. In this study, we report on the development of new derivatives in which we methylated either position 4 of olivetol or the phenolic positions of olivetol, or both. We introduce a refinement on previously reported chemical procedures for phytocannabinoid derivatization as well as the biological evaluation of all derivatives in anti-inflammatory in vivo models. Compounds such as the CBD derivative, 2 and the CBG derivative, 11, significantly reduced cytokine levels when compared to their parent compounds. Moreover, both of these derivatives proved to be as potent as dexamethasone for the inhibition of IL-1ß. We believe that these new derivatives, as described herein, can be further developed as novel drug candidates for inflammatory conditions.
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Cannabidiol , Cannabidiol/farmacología , Resorcinoles , Antiinflamatorios , CitocinasRESUMEN
The pathophysiology of major depressive disorder (MDD) is diverse and multi-factorial, yet treatment strategies remain limited. While women are twice as likely to develop the disorder as men, many animal model studies of antidepressant response rely solely on male subjects. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. Cannabidiolic Acid-Methyl Ester (CBDA-ME, EPM-301) demonstrated anti-depressive-like effects in male rats. Here, we explored acute effects of CBDA-ME and some possible mediating mechanisms, using a depressive-like genetic animal model, the Wistar-Kyoto (WKY) rat. In Experiment 1, Female WKY rats underwent the Forced swim test (FST) following acute CBDA-ME oral ingestion (1/5/10 mg/kg). In Experiment 2, Male and female WKY rats underwent the FST after injection of CB1 (AM-251) and CB2 (AM-630) receptor antagonists 30 min before acute CBDA-ME ingestion (1 mg/kg, males; 5 mg/kg, females). Serum levels of Brain-Derived Neurotrophic Factor (BDNF), numerous endocannabinoids and hippocampal Fatty Acid Amide Hydrolase (FAAH) levels were assessed. Results indicate that females required higher doses of CBDA-ME (5 and 10 mg/kg) to induce an anti-depressive-like effect in the FST. AM-630 blocked the antidepressant-like effect in females, but not in males. The effect of CBDA-ME in females was accompanied by elevated serum BDNF and some endocannabinoids and low hippocampal expression of FAAH. This study shows a sexually diverse behavioral anti-depressive response to CBDA-ME and possible underlying mechanisms in females, supporting its potential use for treating MDD and related disorders.
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Cannabidiol , Trastorno Depresivo Mayor , Receptor Cannabinoide CB2 , Animales , Femenino , Masculino , Ratas , Factor Neurotrófico Derivado del Encéfalo , Cannabidiol/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Modelos Animales de Enfermedad , Endocannabinoides , Ratas Endogámicas WKY , Receptor Cannabinoide CB2/antagonistas & inhibidoresRESUMEN
Stem cells are defined by their ability to self-renew and differentiate, both shown in multiple studies to be regulated by metabolic processes. To decipher metabolic signatures of self-renewal in blastocyst-derived stem cells, we compared early differentiating embryonic stem cells (ESCs) and their extra-embryonic counterparts, trophoblast (T)SCs to their self-renewing counterparts. A metabolomics analysis pointed to the desaturation of fatty acyl chains as a metabolic signature of differentiating blastocyst-derived SCs via the upregulation of delta-6 desaturase (D6D; FADS2) and delta-5 desaturase (D5D; FADS1), key enzymes in the biosynthesis of polyunsaturated fatty acids (PUFAs). The inhibition of D6D or D5D by specific inhibitors or SiRNA retained stemness in ESCs and TSCs, and attenuated endoplasmic reticulum (ER) stress-related apoptosis. D6D inhibition in ESCs upregulated stearoyl-CoA desaturase-1 (Scd1), essential to maintain ER homeostasis. In TSCs, however, D6D inhibition downregulated Scd1. TSCs show higher Scd1 mRNA expression and high levels of monounsaturated fatty acyl chain products in comparison to ESCs. The addition of oleic acid, the product of Scd1 (essential for ESCs), to culture medium, was detrimental to TSCs. Interestingly, TSCs express a high molecular mass variant of Scd1 protein, hardly expressed by ESCs. Taken together, our data suggest that lipid desaturation is a metabolic regulator of the balance between differentiation and self-renewal of ESCs and TSCs. They point to lipid polydesaturation as a driver of differentiation in both cell types. Monounsaturated fatty acids (MUFAs), essential for ESCs are detrimental to TSCs.
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Metabolómica , Células Madre , Animales , Ratones , Diferenciación Celular , LípidosRESUMEN
The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as osteogenic growth peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts. We show that the OGP effects on osteoblast proliferation, osteoclastogenesis, and macrophage inflammation in vitro, as well as rescue of ovariectomy-induced bone loss and prevention of ear edema in vivo are all abrogated by genetic or pharmacological ablation of CB2. We also demonstrate that OGP binds at CB2 and may act as both an agonist and positive allosteric modulator in the presence of other lipophilic agonists. In premenopausal women, OGP circulating levels significantly decline with age. In adult mice, exogenous administration of OGP completely prevented age-related bone loss. Our findings suggest that OGP attenuates age-related bone loss by maintaining a skeletal CB2 tone. Importantly, they also indicate the occurrence of an endogenous peptide that signals via CB2 receptor in health and disease.
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Histonas , Péptidos y Proteínas de Señalización Intercelular , Osteogénesis , Receptor Cannabinoide CB2 , Animales , Femenino , Histonas/metabolismo , Histonas/farmacología , Hormonas , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Ratones , Osteogénesis/fisiología , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Osteoporosis/prevención & control , Péptidos/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD). The metabolic state of the treated mice on HFD is significantly better than that of vehicle-treated mice, and their liver slices show significantly less steatosis than untreated HFD or CBG-treated ones from HFD mice. We believe that HUM-223, HUM-233 and HUM-234 have the potential for development as novel drug candidates for the treatment of inflammatory conditions, and in the case of HUM-234, potentially for obesity where there is a huge unmet need.
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Analgésicos/síntesis química , Antiinflamatorios/síntesis química , Fármacos Antiobesidad/síntesis química , Cannabinoides/química , Analgésicos/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Hígado Graso/tratamiento farmacológico , Femenino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológicoRESUMEN
A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.
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Cannabidiol/análogos & derivados , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias Experimentales , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Quinonas , Inhibidores de Topoisomerasa II , Animales , Cannabidiol/química , Cannabidiol/uso terapéutico , ADN-Topoisomerasas de Tipo II/metabolismo , Humanos , Ratones , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/enzimología , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Quinonas/química , Quinonas/uso terapéutico , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/uso terapéuticoRESUMEN
BACKGROUND: Adipose tissue plays important roles in health and disease. Given the unique association of visceral adipose tissue with obesity-related metabolic diseases, the distribution of lipids between the major fat depots located in subcutaneous and visceral regions may shed new light on adipose tissue-specific roles in systemic metabolic perturbations. OBJECTIVE: We sought to characterize the lipid networks and unveil differences in the metabolic infrastructure of the 2 adipose tissues that may have functional and nutritional implications. METHODS: Paired visceral and subcutaneous adipose tissue samples were obtained from 17 overweight patients undergoing elective abdominal surgery. Ultra-performance LC-MS was used to measure 18,640 adipose-derived features; 520 were putatively identified. A stem cell model for adipogenesis was used to study the functional implications of the differences found. RESULTS: Our analyses resulted in detailed lipid metabolic maps of the 2 major adipose tissues. They point to a higher accumulation of phosphatidylcholines, triacylglycerols, and diacylglycerols, although lower ceramide concentrations, in subcutaneous tissue. The degree of unsaturation was lower in visceral adipose tissue (VAT) phospholipids, indicating lower unsaturated fatty acid incorporation into adipose tissue. The differential abundance of phosphatidylcholines we found can be attributed at least partially to higher expression of phosphatidylethanolamine methyl transferase (PEMT). PEMT-deficient embryonic stem cells showed a dramatic decrease in adipogenesis, and the resulting adipocytes exhibited lower accumulation of lipid droplets, in line with the lower concentrations of glycerolipids in VAT. Ceramides may inhibit the expression of PEMT by increased insulin resistance, thus potentially suggesting a functional pathway that integrates ceramide, PEMT, and glycerolipid biosynthetic pathways. CONCLUSIONS: Our work unveils differential infrastructure of the lipid networks in visceral and subcutaneous adipose tissues and suggests an integrative pathway, with a discriminative flux between adipose tissues.
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Grasa Intraabdominal/metabolismo , Metabolismo de los Lípidos , Sobrepeso/metabolismo , Grasa Subcutánea/metabolismo , Adulto , Animales , Femenino , Glicerofosfolípidos/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Triglicéridos/metabolismoRESUMEN
Follicular fluid (FF) constitutes the microenvironment of the developing oocyte. We recently characterized its lipid composition and found lipid signatures of positive pregnancy outcome after in vitro fertilization (IVF). In the current study, we aimed to test the hypothesis that unexplained female infertility is related to lipid metabolism, given the lipid signature of positive-outcome IVF patients we previously found. Assuming that FF samples from IVF patients with male factor infertility can represent a non-hindered metabolic microenvironment, we compared them to FF taken from women with unexplained infertility. FF from patients undergoing IVF was examined for its lipid composition. We found highly increased triacylglycerol levels, with a lower abundance of monoacylglycerols, phospholipids and sphingolipids in the FF of patients with unexplained infertility. The alterations in the lipid class accumulation were independent of the body mass index (BMI) and were altogether kept across the age groups. Potential lipid biomarkers for pregnancy outcomes showed a highly discriminative abundance in the FF of unexplained infertility patients. Lipid abundance distinguished IVF patients with unrecognized infertility and provided a potential means for the evaluation of female fertility.
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Líquido Folicular/metabolismo , Glicéridos/metabolismo , Infertilidad Femenina/metabolismo , Adulto , Femenino , Fertilización In Vitro , Humanos , Infertilidad Femenina/terapia , Masculino , Fosfolípidos/metabolismo , Esfingolípidos/metabolismoRESUMEN
Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed.
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Cannabinoides/farmacología , Dronabinol/farmacología , Endocannabinoides/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Agonistas de Receptores de Cannabinoides/farmacología , Glicéridos/metabolismo , Humanos , Alcamidas Poliinsaturadas/metabolismoRESUMEN
Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ(9)-tetrahydrocannabinol (Δ(9)-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ(9)-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ(9)-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ(9)-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.
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Acetatos/farmacología , Antiinflamatorios/farmacología , Cannabidiol/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Acetatos/química , Acetatos/metabolismo , Acetatos/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Cannabidiol/química , Cannabidiol/metabolismo , Cannabidiol/uso terapéutico , Concanavalina A/efectos adversos , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/metabolismo , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Citoprotección/efectos de los fármacos , Femenino , Hígado/citología , Hígado/efectos de los fármacos , Hígado/lesiones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Óxido Nítrico/biosíntesis , Especies Reactivas de Oxígeno/metabolismo , Receptores de Cannabinoides/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ(9)-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3-4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [(3)H]CP55,940 displacement and its effect on [(35)S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [(35)S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.
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Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Células CHO , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/metabolismo , Cannabinoides/química , Cannabinoides/metabolismo , Cricetinae , Cricetulus , Ratones , Ratones Endogámicos C57BL , EstereoisomerismoRESUMEN
Recent studies suggest that the metabolic network is an important part of the molecular circuitry that underlies pluripotency. Of the metabolic pathways that were implicated in the pluripotency balance, "energy" metabolism is particularly notable. Its mechanism of action on pluripotency-regulating genes has been partially elucidated when three metabolites, namely acetate, S-adenosylmethionine, and O-linked ß-N-acetylglucosamine were recently shown to link cytosolic signals to pluripotent gene expression. The cytosolic levels of these metabolites are the result of environmental perturbations, making them sensitive messengers, which are assumed to diffuse through the nuclear pores, being small molecules. Recent work also suggests that the modulation of the levels of these metabolites in pluripotent cells controls the balance between pluripotency and early commitment via epigenetic modifications. Here, we review recent studies that link metabolism and pluripotency via epigenetic modifications that occur through these three metabolites.
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Metabolismo Energético/fisiología , Epigénesis Genética/fisiología , Células Madre Pluripotentes/metabolismo , Acetatos/metabolismo , Acetilglucosamina/metabolismo , Animales , Humanos , Células Madre Pluripotentes/citología , S-Adenosilmetionina/metabolismoRESUMEN
Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and Δ(9) -tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro-computed tomography (µCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.
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Cannabidiol/farmacología , Cannabis/química , Fracturas del Fémur , Curación de Fractura/efectos de los fármacos , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Microtomografía por Rayos X , Animales , Cannabidiol/química , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/tratamiento farmacológico , Fracturas del Fémur/enzimología , Ratones , RatasRESUMEN
Despite the activity of cellular quality-control mechanisms, subsets of mature and newly synthesized polypeptides fail to fold properly and form insoluble aggregates. In some cases, protein aggregation leads to the development of human neurodegenerative maladies, including Alzheimer's and prion diseases. Aggregates of misfolded prion protein (PrP), which appear in cells after exposure to the drug cyclosporin A (CsA), and disease-linked PrP mutants have been found to accumulate in juxtanuclear deposition sites termed 'aggresomes'. Recently, it was shown that cells can contain at least two types of deposition sites for misfolded proteins: a dynamic quality-control compartment, which was termed 'JUNQ', and a site for terminally aggregated proteins called 'IPOD'. Here, we show that CsA-induced PrP aggresomes are dynamic structures that form despite intact proteasome activity, recruit chaperones and dynamically exchange PrP molecules with the cytosol. These findings define the CsA-PrP aggresome as a JUNQ-like dynamic quality-control compartment that mediates the refolding or degradation of misfolded proteins. Together, our data suggest that the formation of PrP aggresomes protects cells from proteotoxic stress.
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Ciclosporina/farmacología , Cuerpos de Inclusión/metabolismo , Priones/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Cristalinas/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Complejos Multiproteicos/metabolismo , Enfermedades por Prión/metabolismo , Priones/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Pliegue de Proteína , Ubiquitina/metabolismo , Proteínas Ubiquitinadas/metabolismoRESUMEN
The oxidation of cannabis constituents has given rise to their corresponding quinones, which have been identified as cytotoxic agents. Out of these molecules the quinone of cannabidiol--the most abundant non-psychoactive cannabinoid in Cannabis sativa--has shown the highest cytotoxicity. This compound was named HU-331 and it exerts antiangiogenic properties, induces apoptosis to endothelial cells and inhibits topoisomerase II in nanomolar concentrations. Unlike other quinones, it is not cardiotoxic and does not induce the formation of free radicals. A comparative in vivo study in mice has shown HU-331 to be less toxic and more effective than the commonly used doxorubicin. This review summarises the properties of HU-331 and compares it with doxorubicin and other topoisomerase II inhibitors.
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Cannabidiol/análogos & derivados , Cannabinoides/farmacología , Citotoxinas/farmacología , Quinonas/farmacología , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacología , Animales , Cannabidiol/efectos adversos , Cannabidiol/química , Cannabidiol/farmacología , Cannabinoides/química , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Citotoxinas/efectos adversos , Citotoxinas/química , Humanos , Quinonas/química , Células Tumorales CultivadasRESUMEN
Several quinones have been found to be effective in the treatment of some forms of cancer; however, their cumulative heart toxicity limits their use. The cannabinoid quinone HU-331 [3S,4R-p-benzoquinone-3-hydroxy-2-p-mentha-(1,8)-dien-3-yl-5-pentyl] is highly effective against tumor xenografts in nude mice. We report now a comparison of the anticancer activity of HU-331 and its cardiotoxicity with those of doxorubicin in vivo. General toxicity was assayed in Sabra, nude and SCID-NOD mice. The anticancer activity in vivo was assessed by measurement of the tumors with an external caliper in HT-29 and Raji tumor-bearing mice and by weighing the excised tumors. Left ventricular function was evaluated with transthoracic echocardiography. Myelotoxicity was evaluated by blood cell count. Cardiac troponin T (cTnT) plasma levels were determined by immunoassay. HU-331 was found to be much less cardiotoxic than doxorubicin. The control and the HU-331-treated groups gained weight, whereas the doxorubicin-treated group lost weight during the study. In HT-29 colon carcinoma, the tumor weight in the HU-331-treated group was 54% smaller than in the control group and 30% smaller than in the doxorubicin-treated group. In Raji lymphoma, the tumor weight in the HU-331-treated group was 65% smaller than in the control group and 33% smaller than in the doxorubicin-treated group. In contrast to doxorubicin, HU-331 did not generate reactive oxygen species in mice hearts (measured by protein carbonylation levels and malondialdehyde levels). In vivo, HU-331 was more active and less toxic than doxorubicin and thus it has a high potential for development as a new anticancer drug.
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Cannabidiol/análogos & derivados , Doxorrubicina/farmacología , Corazón/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Recuento de Células Sanguíneas , Peso Corporal/efectos de los fármacos , Cannabidiol/química , Cannabidiol/farmacología , Línea Celular Tumoral , Doxorrubicina/química , Ecocardiografía , Células HT29 , Corazón/fisiopatología , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Endogámicos , Ratones Desnudos , Ratones SCID , Estructura Molecular , Miocardio/metabolismo , Miocardio/patología , Neoplasias/sangre , Neoplasias/patología , Carbonilación Proteica/efectos de los fármacos , Troponina T/sangre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer. Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms. A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice. In this study, we investigated its mode of action and present evidence on its unique mechanism. HU-331 does not cause cancer cell cycle arrest, cell apoptosis, or caspase activation. HU-331-caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations but has only a slight nonsignificant effect on DNA topoisomerase I action. The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones. It might represent a new potent anticancer drug.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cannabidiol/análogos & derivados , Proteínas de Unión al ADN/antagonistas & inhibidores , Inhibidores de Topoisomerasa II , Antígenos de Neoplasias , Apoptosis/efectos de los fármacos , Cannabidiol/química , Cannabidiol/farmacología , Antagonistas de Receptores de Cannabinoides , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Roturas del ADN , ADN-Topoisomerasas de Tipo II , ADN de Neoplasias/química , ADN de Neoplasias/genética , Células HT29 , Humanos , Células Jurkat , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Conformación de Ácido Nucleico , Especies Reactivas de Oxígeno/metabolismo , Receptores de Cannabinoides/metabolismoRESUMEN
Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.