RESUMEN
Through the eons of time, out of all possible configurations, nature has selected glucose not only as a vital source of energy to sustain life but also as the molecule who's structure supplies the appropriate elements required for a cell to grow and multiply. This understanding, at least in part, explains the profound effects that the analog of glucose, 2-deoxy-d-glucose, has been shown to have on as common and widespread diseases as cancer, viral infection, aging-related morbidity, epilepsy, and others. This review is confined to summarizing some of the salient findings of this remarkable compound as they relate mainly to cancer.
Asunto(s)
Desoxiglucosa/metabolismo , Estrés del Retículo Endoplásmico/genética , Neoplasias/metabolismo , Replicación Viral/genética , Apoptosis/genética , Autofagia/genética , Desoxiglucosa/genética , Glicosilación , Humanos , Hipoxia , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas de la Membrana/fisiología , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteína bcl-X/fisiología , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de la Membrana/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/farmacología , Sulfonamidas/farmacología , Distribución Tisular , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. METHODS: MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. FINDINGS: We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score. INTERPRETATION: In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. FUNDING: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.
Asunto(s)
Miastenia Gravis , Receptores Quiméricos de Antígenos , Adolescente , Adulto , Femenino , Humanos , Masculino , Actividades Cotidianas , Autoanticuerpos , Tratamiento Basado en Trasplante de Células y Tejidos , Síndrome de Liberación de Citoquinas , Miastenia Gravis/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Receptores Quiméricos de Antígenos/uso terapéutico , Resultado del TratamientoRESUMEN
Lytic replication of the Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of Kaposi's sarcoma and thus represents a desirable therapeutic target. During the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (ER). Normally, this leads to ER stress which, through an unfolded protein response (UPR), triggers phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), resulting in inhibition of protein synthesis to maintain ER and cellular homeostasis. However, in order to replicate, herpesviruses have acquired the ability to prevent eIF2α phosphorylation. Here we show that clinically achievable nontoxic doses of the glucose analog 2-deoxy-d-glucose (2-DG) stimulate ER stress, thereby shutting down eIF2α and inhibiting KSHV and murine herpesvirus 68 replication and KSHV reactivation from latency. Viral cascade genes that are involved in reactivation, including the master transactivator (RTA) gene, glycoprotein B, K8.1, and angiogenesis-regulating genes are markedly decreased with 2-DG treatment. Overall, our data suggest that activation of UPR by 2-DG elicits an early antiviral response via eIF2α inactivation, which impairs protein synthesis required to drive viral replication and oncogenesis. Thus, induction of ER stress by 2-DG provides a new antiherpesviral strategy that may be applicable to other viruses.
Asunto(s)
Antivirales/farmacología , Desoxiglucosa/farmacología , Retículo Endoplásmico/efectos de los fármacos , Factor 2 Eucariótico de Iniciación/antagonistas & inhibidores , Herpesvirus Humano 8/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Retículo Endoplásmico/genética , Retículo Endoplásmico/virología , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Expresión Génica/efectos de los fármacos , Herpesvirus Humano 8/fisiología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Ratones , Fosforilación , Activación Transcripcional/efectos de los fármacos , Respuesta de Proteína Desplegada/genética , Ensayo de Placa Viral , Proteínas Virales/biosíntesis , Proteínas Virales/genética , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Chimeric antigen receptor (CAR) T-cell therapy remains limited to select centers that can carefully monitor adverse events. To broaden use of CAR T cells in community clinics and in a frontline setting, we developed a novel CD8+ CAR T-cell product, Descartes-08, with predictable pharmacokinetics for treatment of multiple myeloma. Descartes-08 is engineered by mRNA transfection to express anti-BCMA CAR for a defined length of time. Descartes-08 expresses anti-BCMA CAR for 1 week, limiting risk of uncontrolled proliferation; produce inflammatory cytokines in response to myeloma target cells; and are highly cytolytic against myeloma cells regardless of the presence of myeloma-protecting bone marrow stromal cells, exogenous a proliferation-inducing ligand, or drug resistance including IMiDs. The magnitude of cytolysis correlates with anti-BCMA CAR expression duration, indicating a temporal limit in activity. In the mouse model of aggressive disseminated human myeloma, Descartes-08 induces BCMA CAR-specific myeloma growth inhibition and significantly prolongs host survival (p < 0.0001). These preclinical data, coupled with an ongoing clinical trial of Descartes-08 in relapsed/refractory myeloma (NCT03448978) showing preliminary durable responses and a favorable therapeutic index, have provided the framework for a recently initiated trial of an optimized/humanized version of Descartes-08 (i.e., Descartes-11) in newly diagnosed myeloma patients with residual disease after induction therapy.
Asunto(s)
Antígeno de Maduración de Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/terapia , ARN Mensajero/genética , Receptores Quiméricos de Antígenos/inmunología , Animales , Apoptosis , Antígeno de Maduración de Linfocitos B/genética , Proliferación Celular , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mieloma Múltiple/inmunología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immunoglobulin G (IgG) is the most abundant serum antibody which structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. Composition of the IgG N-glycome changes with age of an individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is known to be affected by both genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG's fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability. IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.
Asunto(s)
Envejecimiento/sangre , Inmunoglobulina G/sangre , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Femenino , Salud Global , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1alpha) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1alpha translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1alpha down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1alpha. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.
Asunto(s)
Desoxiglucosa/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/enzimología , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Pulmonares/patología , Mutación/genética , ARN Interferente Pequeño/farmacología , Sirolimus/análogos & derivados , Sirolimus/farmacología , Serina-Treonina Quinasas TORRESUMEN
Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-d-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF(+)) or absence (HIF(-)) of hypoxia, (b) cells treated with small interfering RNA specific for HIF-1alpha and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF(+) counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.
Asunto(s)
Antimetabolitos/farmacología , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Desoxiglucosa/farmacología , Resistencia a Antineoplásicos , Subunidad alfa del Factor 1 Inducible por Hipoxia/farmacología , Adenosina Trifosfato/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Glucosa-6-Fosfato Isomerasa/metabolismo , Glucólisis , Células HeLa , Hexoquinasa/metabolismo , Humanos , Immunoblotting , Ácido Láctico/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Plásmidos , ARN Mensajero , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.
Asunto(s)
Desoxiglucosa/farmacología , Glucólisis/efectos de los fármacos , Neoplasias/patología , Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo , Aerobiosis/efectos de los fármacos , Anaerobiosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fluorodesoxiglucosa F18/farmacología , Glicosilación/efectos de los fármacos , Humanos , Manosa/farmacología , Modelos Biológicos , Oligosacáridos/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Pliegue de Proteína , Factor de Transcripción CHOP/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The dependence of hypoxic tumor cells on glycolysis as their main means of producing ATP provides a selective target for agents that block this pathway, such as 2-deoxy-D-glucose (2-DG) and 2-fluoro-deoxy-D-glucose (2-FDG). Moreover, it was demonstrated that 2-FDG is a more potent glycolytic inhibitor with greater cytotoxic activity than 2-DG. This activity correlates with the closer structural similarity of 2-FDG to glucose than 2-DG, which makes it a better inhibitor of hexokinase, the first enzyme in the glycolytic pathway. In contrast, because of its structural similarity to mannose, 2-DG is known to be more effective than 2-FDG in interfering with N-linked glycosylation. Recently, it was reported that 2-DG, at a relatively low dose, is toxic to certain tumor cells, even under aerobic conditions, whereas 2-FDG is not. These results indicate that the toxic effects of 2-DG in selected tumor cells under aerobic conditions is through inhibition of glycosylation rather than glycolysis. The intention of this minireview is to discuss the effects and potential clinical impact of 2-DG and 2-FDG as antitumor agents and to clarify the differential mechanisms by which these two glucose analogues produce toxicity in tumor cells growing under anaerobic or aerobic conditions.
Asunto(s)
Hipoxia de la Célula/fisiología , Desoxiglucosa/toxicidad , Neoplasias/fisiopatología , Anaerobiosis , Glucólisis , Humanos , Modelos Biológicos , Neoplasias/patología , Consumo de Oxígeno/efectos de los fármacosRESUMEN
PURPOSE: Since 2-deoxy-D-glucose (2-DG) is currently in phase I clinical trials to selectively target slow-growing hypoxic tumor cells, 2-halogenated D-glucose analogs were synthesized for improved activity. Given the fact that 2-DG competes with D-glucose for binding to hexokinase, in silico modeling of molecular interactions between hexokinase I and these new analogs was used to determine whether binding energies correlate with biological effects, i.e. inhibition of glycolysis and subsequent toxicity in hypoxic tumor cells. METHODS AND RESULTS: Using a QSAR-like approach along with a flexible docking strategy, it was determined that the binding affinities of the analogs to hexokinase I decrease as a function of increasing halogen size as follows: 2-fluoro-2-deoxy-D-glucose (2-FG) > 2-chloro-2-deoxy-D-glucose (2-CG) > 2-bromo-2-deoxy-D-glucose (2-BG). Furthermore, D-glucose was found to have the highest affinity followed by 2-FG and 2-DG, respectively. Similarly, flow cytometry and trypan blue exclusion assays showed that the efficacy of the halogenated analogs in preferentially inhibiting growth and killing hypoxic vs. aerobic cells increases as a function of their relative binding affinities. These results correlate with the inhibition of glycolysis as measured by lactate inhibition, i.e. ID50 1 mM for 2-FG, 6 mM for 2-CG and > 6 mM for 2-BG. Moreover, 2-FG was found to be more potent than 2-DG for both glycolytic inhibition and cytotoxicity. CONCLUSIONS: Overall, our in vitro results suggest that 2-FG is more potent than 2-DG in killing hypoxic tumor cells, and therefore may be more clinically effective when combined with standard chemotherapeutic protocols.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Desoxiglucosa/farmacología , Glucólisis/efectos de los fármacos , Halógenos/química , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Desoxiglucosa/análogos & derivados , Desoxiglucosa/química , Diseño de Fármacos , Fluorodesoxiglucosa F18/química , Fluorodesoxiglucosa F18/farmacología , Glucosa-6-Fosfato/análogos & derivados , Glucosa-6-Fosfato/química , Glucosa-6-Fosfato/metabolismo , Hexoquinasa/química , Hexoquinasa/metabolismo , Humanos , Ácido Láctico/química , Ácido Láctico/metabolismo , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , TermodinámicaRESUMEN
One of the key factors that correlates with poor survival of patients with pancreatic cancer is the extent of hypoxic areas within the tumor tissue. The adaptation of pancreatic cancer cells to limited oxygen delivery promotes the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development, which resist in most cases adjuvant therapies following tumor resection. In this article, the authors summarize the evidence demonstrating the significance of hypoxia in pancreatic cancer pathogenesis and discuss the possible hypoxia-induced mechanisms underlying its aggressive nature. We then conclude with promising strategies that target hypoxia-adapted pancreatic cancer cells.
Asunto(s)
Oxígeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral , Animales , Antineoplásicos/uso terapéutico , Hipoxia de la Célula , Diseño de Fármacos , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Terapia Molecular Dirigida , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Fenotipo , Transducción de SeñalRESUMEN
Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.
Asunto(s)
Apoptosis/efectos de los fármacos , Desoxiglucosa/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fenofibrato/farmacología , Glucólisis/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Línea Celular Tumoral , Sinergismo Farmacológico , Chaperón BiP del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Femenino , Proteínas de Choque Térmico/metabolismo , Humanos , Hipolipemiantes/farmacología , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in vitro, patients with advanced urothelial carcinomas continue to have poor clinical outcomes. In the present review, we focus on targeted therapies that have yielded the most promising results alone or combined with traditional chemotherapy, including the antiangiogenesis agent bevacizumab, the human epidermal growth factor receptor 2 antibody trastuzumab, and the tyrosine kinase inhibitor cabozantinib. We also describe ongoing and developing clinical trials that use innovative approaches, including dose-dense scheduling of singular chemotherapy combinations, prospective screening of tumor tissues for mutational targets and biomarkers to predict chemosensitivity before the determination of the therapeutic regimen, and novel agents that target proteins in the immune checkpoint regulation pathway (programmed cell death protein 1 [PD-1] and anti-PD-ligand 1) that have shown significant potential in preclinical models and early clinical trials. New agents and targeted therapies, alone or combined with traditional chemotherapy, will only be validated through accrual to developing clinical trials that aim to translate these therapies into individualized treatments and improved survival rates in urothelial carcinoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Urológicas/tratamiento farmacológico , Anilidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Ensayos Clínicos como Asunto , Humanos , Medicina de Precisión , Piridinas/uso terapéutico , Trastuzumab/uso terapéutico , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , Urotelio/efectos de los fármacos , Urotelio/patologíaRESUMEN
Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations.
RESUMEN
BACKGROUND: In our study we aimed to evaluate, retrospectively, the bleeding and the Venousthrombo Emblism (VTE) complications in trauma patients in Intensive Care Unit (ICU) under the prophylaxis of enoxaparin sodium. The results will guide us to establish a protocol for use of Enoxaparin Sodium in trauma patients. In trauma patients, Low Molecular Weight Heparine (LMWH) has better efficiency than unfractionned heparin and intermittant pneumatic compression for VTE prophylaxis. METHODS: 457 polytraumatized patients treated in ICU are included to the study group. All patients received 40 mg/day of Enoxaparin Sodium. Severity of trauma was assessed with Apache II Scoring System and bleeding diagnosed by observing a sudden drop of 2 g/dl in hemoglobin concentration and pulmonary embolism was diagnosed by a sudden change in blood gases and deterioration of the clinical outlook which was confirmed by a spiral CT scan. Statistical correlation was made by Pearson's correlation test. RESULTS: Mean Apache II score was 13.8 with a total mortality of 41%. 42 patients (9,2%) had bleeding due to Enoxiparine Sodium prophylaxis. 12 patients (2,6%) had pulmonary embolism and 8 of them (1,7%) had died. CONCLUSION: Verified by the literature and our study, LMWH prophylaxis significantly reduces the Pulmoner Embolism (PE) incidence in polytraumatized patients (p<0,05). On the other hand, the bleeding risk has slightly increased without showing any significance (p>0.05). Prophylaxis with LMWH is safe and efficient in polytraumatized ICU patients.
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Anticoagulantes/efectos adversos , Enoxaparina/efectos adversos , Hemorragia/mortalidad , Traumatismo Múltiple/patología , Embolia Pulmonar/mortalidad , Trombosis de la Vena/prevención & control , APACHE , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hemorragia/inducido químicamente , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Turquía/epidemiologíaRESUMEN
PURPOSE: Although cisplatin is the drug of choice in treating lung cancer patients, relapse and resistance is a common drawback to its clinical effectiveness. Based on cisplatin's reported ability to interfere with numerous cellular components, including mitochondria, we probed alterations in metabolism in cisplatin-resistant tumor cell lines to reveal targets for overcoming this important form of resistance. METHODS: Cisplatin-resistant lung and ovarian cancer cell lines were used to evaluate the efficacy of metabolic inhibitors for selectively targeting cisplatin-resistant cells under varying oxygen conditions. RESULTS: Three cisplatin-resistant cancer cell lines expressed lower HKII protein when compared to the respective cisplatin-sensitive cancer cell lines from which they were derived. Under anaerobic and hypoxic conditions, treatment with the glycolytic inhibitors 2-deoxyglucose (2-DG) and 2-fluorodeoxyglucose (2-FDG) correlated with increased cytotoxicity and more pronounced decreases in lactate production in cisplatin-resistant cells, indicating a greater blockage of glycolysis. Knockdown of HKI or HKII with siRNA in the parental lung cancer cell lines led to increased 2-FDG-induced cell death under anaerobic conditions. Under normal oxygen conditions, blockage of either fatty acid oxidation or deprivation of glutamine resulted in cell death in cisplatin-resistant lung cancer cell lines. CONCLUSIONS: Altered hexokinase levels in cisplatin-resistant cancer cell lines leads to increased sensitivity to glycolytic inhibition under anaerobic conditions, whereas under normoxic conditions, blockage of either fatty acid oxidation or deprivation of glutamine leads to cell death. These findings may be clinically applicable when considering cisplatin resistance.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Desoxiglucosa/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Glucólisis/efectos de los fármacos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Ácido Láctico/metabolismo , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , TransfecciónRESUMEN
BACKGROUND: As tumors evolve, they upregulate glucose metabolism while also encountering intermittent periods of glucose deprivation. Here, we investigate mechanisms by which pancreatic cancer cells respond to therapeutic (2-deoxy-D-glucose, 2-DG) and physiologic (glucose starvation, GS) forms of glucose restriction. METHODS: From a tumor cell line (1420) that is unusually sensitive to 2-DG under normoxia, low (14DG2)- and high (14DG5)-dose resistant cell lines were selected and used to probe the metabolic pathways involved with their response to different forms of glucose deprivation. RESULTS: Muted induction of the unfolded protein response was found to correlate with resistance to 2-DG. Additionally, 14DG2 displayed reduced 2-DG uptake, while 14DG5 was cross-resistant to tunicamycin, suggesting it has enhanced ability to manage glycosylation defects. Conversely, 2-DG-resistant cell lines were more sensitive than their parental cell line to GS, which coincided with lowered levels of glycogen phosphorylase (PYGB) and reduced breakdown of glycogen to glucose in the 2-DG-resistant cell lines. Moreover, by inhibiting PYGB in the parental cell line, sensitivity to GS was increased. CONCLUSIONS: Overall, the data demonstrate that the manner in which glucose is restricted in tumor cells, i.e., therapeutic or physiologic, leads to differential biological responses involving distinct glucose metabolic pathways. Moreover, in evolving tumors where glucose restriction occurs, the identification of PYGB as a metabolic target may have clinical application.
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Desoxiglucosa/farmacología , Glucosa/deficiencia , Glucosa/metabolismo , Glucógeno Fosforilasa/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Glucólisis , Humanos , Isoenzimas , Neoplasias Pancreáticas/enzimología , Respuesta de Proteína DesplegadaRESUMEN
BACKGROUND: Inhibition of glucose metabolism has recently become an attractive target for cancer treatment. Accordingly, since 2-deoxyglucose (2-DG) competes effectively with glucose, it has come under increasing scrutiny as a therapeutic agent. The initial response of tumor cells to 2-DG is growth inhibition, which is thought to conserve energy and consequently protect cells from its ATP-lowering effects as a glycolytic inhibitor. However, since 2-DG also mimics mannose and thereby interferes with N-linked glycosylation, the question is raised of how this sugar analog inhibits tumor cell growth and whether the mechanism by which it protects cells can be manipulated to convert 2-DG-induced growth inhibition to cell death. METHODS: Cell growth and death were measured via counting viable and dead cells based on trypan blue exclusion. Markers of ATP reduction and the unfolded protein response (UPR) were detected by Western blot. Protein functions were manipulated through chemical compounds, siRNA and the use of gene-specific wild-type and knock-out mouse embryonic fibroblasts (MEFs). RESULTS: At 2-DG concentrations that can be achieved in human plasma without causing significant side effects, we find (a) It induces growth inhibition predominantly by interference with glycosylation, which leads to accumulation of unfolded proteins in the endoplasmic reticulum activating the UPR; (b) Inhibition of PERK (but not ATF6 or IRE1), a major component of the UPR, leads to conversion of 2-DG-induced growth inhibition to cell death and (c) secondarily to PERK, inhibition of GCN2, a kinase that is activated in response to low intracellular glutamine, increases 2-DG's cytotoxic effects in PERK -/- MEFs. CONCLUSIONS: Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG's static effect to a toxic one in tumor cells growing under normoxia.
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Antimetabolitos Antineoplásicos/farmacología , Desoxiglucosa/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Respuesta de Proteína Desplegada/efectos de los fármacos , eIF-2 Quinasa/antagonistas & inhibidores , Factor de Transcripción Activador 6/antagonistas & inhibidores , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Animales , Biomarcadores/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Glicosilación/efectos de los fármacos , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
PURPOSE: This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors. METHODS: A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m(2) for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles. RESULTS: Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel. CONCLUSION: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.