RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted adenosine monophosphate-activated serine/threonine protein kinase (AMPK) activation and downregulation of mammalian target of rapamycin (mTOR) signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL patient-derived xenografts (PDXs) led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47-driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
Asunto(s)
Antineoplásicos/uso terapéutico , Mitocondrias/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Desacopladores/uso terapéutico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Mitocondrias/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Desacopladores/farmacologíaRESUMEN
BACKGROUND: Mitochondrial uncouplers are well-known for their ability to treat a myriad of metabolic diseases, including obesity and fatty liver diseases. However, for many years now, mitochondrial uncouplers have also been evaluated in diverse models of cancer in vitro and in vivo. Furthermore, some mitochondrial uncouplers are now in clinical trials for cancer, although none have yet been approved for the treatment of cancer. SCOPE OF REVIEW: In this review we summarise published studies in which mitochondrial uncouplers have been investigated as an anti-cancer therapy in preclinical models. In many cases, mitochondrial uncouplers show strong anti-cancer effects both as single agents, and in combination therapies, and some are more toxic to cancer cells than normal cells. Furthermore, the mitochondrial uncoupling mechanism of action in cancer cells has been described in detail, with consistencies and inconsistencies between different structural classes of uncouplers. For example, many mitochondrial uncouplers decrease ATP levels and disrupt key metabolic signalling pathways such as AMPK/mTOR but have different effects on reactive oxygen species (ROS) production. Many of these effects oppose aberrant phenotypes common in cancer cells that ultimately result in cell death. We also highlight several gaps in knowledge that need to be addressed before we have a clear direction and strategy for applying mitochondrial uncouplers as anti-cancer agents. MAJOR CONCLUSIONS: There is a large body of evidence supporting the therapeutic use of mitochondrial uncouplers to treat cancer. However, the long-term safety of some uncouplers remains in question and it will be critical to identify which patients and cancer types would benefit most from these agents.
Asunto(s)
Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Desacopladores/uso terapéutico , Adenosina Trifosfato/metabolismo , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Humanos , Mitocondrias/metabolismo , Neoplasias/patología , Fosforilación Oxidativa/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral/efectos de los fármacos , Desacopladores/farmacología , Efecto Warburg en Oncología/efectos de los fármacosRESUMEN
Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.
Asunto(s)
Diaminas/uso terapéutico , Mitocondrias Hepáticas/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pirazinas/uso terapéutico , Desacopladores/uso terapéutico , Animales , Diaminas/química , Diaminas/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oxadiazoles/química , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Consumo de Oxígeno/efectos de los fármacos , Pirazinas/química , Pirazinas/farmacología , Desacopladores/química , Desacopladores/farmacologíaRESUMEN
Mitochondrial dysfunction is thought to be involved in the pathogenesis of MS and here we tested if brain penetrant mitochondrial uncouplers, DNP (MP101) and a novel prodrug of DNP (MP201), have the pharmacology to suppress demyelination and axonal loss in two independent models of MS by modulating the entire organelle's physiology. First, the gold standard EAE mouse model for MS was evaluated by daily oral treatment Day 7-21 with either MP101 or MP201 post-immunization. Both MP101/MP201 significantly suppressed progression of paralysis with limited infiltration of inflammatory cells. Strikingly, although mitochondrial uncouplers do increase energy expenditure even at the low doses provided here, they paradoxically preserved body weight at all doses in comparison to wasting in advanced paralysis of the placebos. Second, the effects of the compounds on suppressing inflammation were also evaluated in the cuprizone model, independent of the immune system. MP101/MP201 had a striking effect preserving both myelination and protecting the axons, in comparison to the placebos where both were destroyed. Both MP101/MP201 induced a significant and sustained increase in neurotrophin, BDNF, in the spinal cords. Both MP101/MP201 suppressed the expression of inflammatory cytokines including IL-1ß, TNF-α and iNOS. Results indicate that MP101/MP201 may be a "disease modifying" treatment for MS by specifically modulating mitochondrial physiology. This would be a completely novel treatment for MS, targeting the mitochondria directly using a unique platform, mitochondrial uncouplers, that initially act non-genomically based upon biophysics, but cascades into cellular remodeling, neuroprotection and pro-survival. Clinical Phase I testing of MP101 in Normal Healthy Volunteers (NHV) is currently underway allowing for the potential to subsequently evaluate translation in MS patients and other insidious diseases, at expected weight neutral doses.
Asunto(s)
2,4-Dinitrofenol/análogos & derivados , Mitocondrias/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Profármacos/uso terapéutico , Desacopladores/uso terapéutico , 2,4-Dinitrofenol/farmacología , 2,4-Dinitrofenol/uso terapéutico , Animales , Axones/efectos de los fármacos , Axones/patología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Cuprizona , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Preparaciones de Acción Retardada , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Encefalitis/patología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Femenino , Inmunización , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/patología , Factores de Crecimiento Nervioso/biosíntesis , Parálisis/inducido químicamente , Parálisis/tratamiento farmacológico , Profármacos/farmacologíaRESUMEN
BACKGROUND: 1,4-naphthoquinones, especially juglone, are known for their anticancer activity. However, plumbagin, lawsone, and menadione have been less investigated for these properties. Therefore, we aimed to determine the effects of plumbagin, lawsone, and menadione on C6 glioblastoma cell viability, ROS production, and mitochondrial function. METHODS: Cell viability was assessed spectrophotometrically using metabolic activity method, and by fluorescent Hoechst/propidium iodide nuclear staining. ROS generation was measured fluorometrically using DCFH-DA. Oxygen uptake rates were recorded by the high-resolution respirometer Oxygraph-2k. RESULTS: Plumbagin and menadione displayed highly cytotoxic activity on C6 cells (IC50 is 7.7 ± 0.28 µM and 9.6 ± 0.75 µM, respectively) and caused cell death by necrosis. Additionally, they increased the amount of intracellular ROS in a concentration-dependent manner. Moreover, even at very small concentrations (1-3 µM), these compounds significantly uncoupled mitochondrial oxidation from phosphorylation impairing energy production in cells. Lawsone had significantly lower viability decreasing and mitochondria-uncoupling effect, and exerted strong antioxidant activity. CONCLUSIONS: Plumbagin and menadione exhibit strong prooxidant, mitochondrial oxidative phosphorylation uncoupling and cytotoxic activity. In contrast, lawsone demonstrates a moderate effect on C6 cell viability and mitochondrial functions, and possesses strong antioxidant properties.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Glioblastoma/metabolismo , Mitocondrias/efectos de los fármacos , Naftoquinonas/farmacología , Oxidantes/farmacología , Desacopladores/farmacología , Animales , Antineoplásicos/uso terapéutico , Antioxidantes/uso terapéutico , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Glioblastoma/tratamiento farmacológico , Mitocondrias/metabolismo , Naftoquinonas/uso terapéutico , Oxidantes/uso terapéutico , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Especies Reactivas de Oxígeno/metabolismo , Desacopladores/uso terapéutico , Vitamina K 3/farmacología , Vitamina K 3/uso terapéuticoRESUMEN
Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.
Asunto(s)
Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Desacopladores/farmacología , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Cricetulus , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Modelos Animales de Enfermedad , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/patología , Femenino , Células Hep G2 , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/mortalidad , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Riñón/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Análisis de Supervivencia , Desacopladores/farmacocinética , Desacopladores/uso terapéuticoRESUMEN
BACKGROUND/AIMS: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. METHODS: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. RESULTS: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. CONCLUSION: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.
Asunto(s)
Lesión Renal Aguda/prevención & control , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Rotenona/uso terapéutico , Acetaminofén/efectos adversos , Lesión Renal Aguda/inducido químicamente , Animales , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Ratones , Sustancias Protectoras , Rotenona/farmacología , Desacopladores/farmacología , Desacopladores/uso terapéuticoRESUMEN
From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted "one-size fits all" approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non-replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory "uncouplers" disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development.
Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Metabolismo Energético/efectos de los fármacos , Mycobacterium tuberculosis/fisiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Diarilquinolinas/farmacología , Diarilquinolinas/uso terapéutico , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Farmacorresistencia Bacteriana Múltiple , Complejo I de Transporte de Electrón , Humanos , Potenciales de la Membrana/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Mycobacterium tuberculosis/efectos de los fármacos , ATPasas de Translocación de Protón/antagonistas & inhibidores , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Desacopladores/farmacología , Desacopladores/uso terapéuticoRESUMEN
Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.
Asunto(s)
Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Proteínas del Choque Térmico HSP40/metabolismo , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales/metabolismo , Chaperonas Moleculares/metabolismo , Adolescente , Adulto , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Modelos Animales de Enfermedad , Sobredosis de Droga/complicaciones , Sobredosis de Droga/etiología , Complejo I de Transporte de Electrón/metabolismo , Femenino , Técnicas de Inactivación de Genes , Proteínas del Choque Térmico HSP40/antagonistas & inhibidores , Hepatocitos , Humanos , Hígado/citología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/genética , Chaperonas Moleculares/antagonistas & inhibidores , Chaperonas Moleculares/genética , Cultivo Primario de Células , ARN Interferente Pequeño/metabolismo , Rotenona/farmacología , Rotenona/uso terapéutico , Desacopladores/farmacología , Desacopladores/uso terapéutico , Adulto JovenRESUMEN
MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.
Asunto(s)
Acetofenonas/uso terapéutico , Antineoplásicos/uso terapéutico , Benzopiranos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Desacopladores/uso terapéutico , Acetofenonas/efectos adversos , Acetofenonas/química , Acetofenonas/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacología , Benzopiranos/efectos adversos , Benzopiranos/química , Benzopiranos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Genes Reporteros/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Neoplasias Hepáticas Experimentales/prevención & control , Neoplasias Hepáticas Experimentales/secundario , Ratones SCID , Simulación del Acoplamiento Molecular , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Distribución Aleatoria , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequeñas , Transactivadores , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Carga Tumoral/efectos de los fármacos , Desacopladores/efectos adversos , Desacopladores/química , Desacopladores/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor hypoxia has long been considered as a detrimental factor for the response to irradiation. In order to improve the sensitivity of tumors cells to radiation therapy, tumor hypoxia may theoretically be alleviated by increasing the oxygen delivery or by decreasing the oxygen consumption by tumor cells. Mathematical modelling suggested that decreasing the oxygen consumption should be more efficient than increasing oxygen delivery in order to alleviate tumor hypoxia. In this paper, we review several promising strategies targeting the mitochondrial respiration for which alleviation of tumor hypoxia and increase in sensitivity to irradiation have been demonstrated. Because the translation of these approaches into the clinical arena requires the use of pharmacodynamics biomarkers able to identify shift in oxygen consumption and tumor oxygenation, we also discuss the relative merits of imaging biomarkers (Positron Emission Tomography and Magnetic Resonance) that may be used for therapeutic guidance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Asunto(s)
Antineoplásicos/farmacología , Mitocondrias/metabolismo , Neoplasias/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Tolerancia a Radiación/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Hipoxia de la Célula/efectos de los fármacos , Terapia Combinada , Humanos , Oxigenoterapia Hiperbárica , Mitocondrias/efectos de los fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Oxígeno/farmacología , Oxígeno/uso terapéutico , Microambiente Tumoral , Desacopladores/farmacología , Desacopladores/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochondria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the development of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the 'contract of endosymbiosis' represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This important property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Asunto(s)
Mitocondrias/metabolismo , Proteínas Desacopladoras Mitocondriales/fisiología , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacocinética , Hipoxia de la Célula , Línea Celular Tumoral , Reprogramación Celular , Resistencia a Antineoplásicos/fisiología , Sinergismo Farmacológico , Metabolismo Energético , Humanos , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Proteínas de Neoplasias/fisiología , Neoplasias/tratamiento farmacológico , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Simbiosis , Desacopladores/farmacología , Desacopladores/uso terapéuticoRESUMEN
Food restriction causes a set of physiological changes that reduce the rate of aging. At the level of an organism, these changes are initiated by a hormonal response, which in turn activates certain intracellular signaling cascades. As a result, cells increase their antioxidant capacities and decrease the risk of cancerous transformation. A number of small molecule compounds activating these signaling cascades have been described. One could expect that direct pharmacological activation of the signaling can produce a stronger antiaging effect than that achieved by the indirect hormonal stimulation. Data from the literature point to the opposite. Possibly, a problem with pharmacological activators is that they cause generation of mitochondrial reactive oxygen species. Indeed, hyperpolarized mitochondria are known to induce oxidative stress. Such hyperpolarization could happen because of artificial activation of cellular response to caloric restriction in the absence of energy deficit. At the same time, energy deficit seems likely to be a natural consequence of the shortage of nutrients. Thus, there is a possibility that combining the pharmacological activators with compounds that decrease mitochondrial transmembrane potential, uncouplers, could be a powerful antiaging strategy.
Asunto(s)
Envejecimiento/efectos de los fármacos , Desacopladores/farmacología , Animales , Hormonas/fisiología , Humanos , Longevidad , Oxidación-Reducción , Fosforilación , Transducción de Señal , Desacopladores/uso terapéuticoRESUMEN
The BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cγ1 (PLCγ1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCγ1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.
Asunto(s)
Fragmentos de Péptidos/uso terapéutico , Fosfolipasa C gamma/metabolismo , Receptor trkB/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/prevención & control , Desacopladores/uso terapéutico , Secuencia de Aminoácidos , Animales , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/prevención & control , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Fragmentos de Péptidos/genética , Fosfolipasa C gamma/genética , Ratas , Ratas Sprague-Dawley , Receptor trkB/genética , Estado Epiléptico/genéticaRESUMEN
Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Mitocondrias/metabolismo , Niclosamida/uso terapéutico , Desacopladores/uso terapéutico , Administración Oral , Animales , Glucemia/metabolismo , Respiración de la Célula/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Ayuno/sangre , Hígado Graso/complicaciones , Hígado Graso/tratamiento farmacológico , Hígado Graso/patología , Técnica de Clampeo de la Glucosa , Células Hep G2 , Humanos , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/patología , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/ultraestructura , Masculino , Mamíferos/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Células 3T3 NIH , Niclosamida/administración & dosificación , Niclosamida/química , Niclosamida/farmacología , Desacopladores/administración & dosificación , Desacopladores/química , Desacopladores/farmacologíaRESUMEN
It has been about 15 years since the introduction of the rechargeable mitochondria-targeted antioxidants (RMA). Two major groups have been developing RMA of the MitoQ and SkQ types independently, and many additional trials have been done by other researchers. This has provided solid preclinical evidence of RMA efficacy in various models. Human trials of systemic MitoQ were not followed by further advances, but the safety of MitoQ and, most likely, other RMA in humans has been demonstrated. A prooxidant effect at higher concentrations of RMA was described. For RMA of the SkQ type, a large window between anti- and prooxidant concentrations was observed, which makes SkQs promising as potential medicines. Significant RMA-induced improvements in many diseases that do not have an accepted treatment have been described. This justifies further clinical trials of RMA.
Asunto(s)
Antioxidantes/uso terapéutico , Mitocondrias/metabolismo , Envejecimiento/patología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Enfermedad , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Mitocondrias/efectos de los fármacos , Desacopladores/farmacología , Desacopladores/uso terapéuticoRESUMEN
The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode's developmental process.
Asunto(s)
Antinematodos/uso terapéutico , Quitinasas/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Ionóforos/uso terapéutico , Onchocerca volvulus/crecimiento & desarrollo , Animales , Caenorhabditis elegans/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Muda/efectos de los fármacos , Onchocerca volvulus/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Salicilanilidas/química , Salicilanilidas/uso terapéutico , Relación Estructura-Actividad , Desacopladores/uso terapéuticoRESUMEN
We investigated the impact of cardiac reactive oxygen species (ROS) during the development of pressure overload-induced heart failure. We used our previously described rat model where transverse aortic constriction (TAC) induces compensated hypertrophy after 2 weeks, heart failure with preserved ejection fraction at 6 and 10 weeks, and heart failure with systolic dysfunction after 20 weeks. We measured mitochondrial ROS production rates, ROS damage and assessed the therapeutic potential of in vivo antioxidant therapies. In compensated hypertrophy (2 weeks of TAC) ROS production rates were normal at both mitochondrial ROS production sites (complexes I and III). Complex I ROS production rates increased with the appearance of diastolic dysfunction (6 weeks of TAC) and remained high thereafter. Surprisingly, maximal ROS production at complex III peaked at 6 weeks of pressure overload. Mitochondrial respiratory capacity (state 3 respiration) was elevated 2 and 6 weeks after TAC, decreased after this point and was significantly impaired at 20 weeks, when contractile function was also impaired and ROS damage was found with increased hydroxynonenal. Treatment with the ROS scavenger α-phenyl-N-tert-butyl nitrone or the uncoupling agent dinitrophenol significantly reduced ROS production rates at 6 weeks. Despite the decline in ROS production capacity, no differences in contractile function between treated and untreated animals were observed. Increased ROS production occurs early in the development of heart failure with a peak at the onset of diastolic dysfunction. However, ROS production may not be related to the onset of contractile dysfunction.