RESUMEN
Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.
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Neoplasias , Adulto , Humanos , Survivin/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Apoptosis , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Asociadas a Microtúbulos/uso terapéuticoRESUMEN
BACKGROUND: Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection. METHODS: Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan-Meier method and compared with the log-rank test. RESULTS: GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044). CONCLUSIONS: Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Survivin/metabolismo , Survivin/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Estudios Retrospectivos , Transportador de Glucosa de Tipo 1 , Pronóstico , Recurrencia Local de Neoplasia , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/uso terapéutico , Apoptosis , Neoplasias Pancreáticas/patologíaRESUMEN
Second mitochondria-derived activator of caspases (SMAC) mimetics are small molecule drugs that mimic the activity of the endogenous SMAC protein. SMAC and SMAC mimetics antagonize inhibitors of apoptosis proteins (IAPs), thereby sensitizing cells to apoptosis. As such, SMAC mimetics are being tested in numerous clinical trials for cancer. In addition to their direct anti-cancer effect, it has been suggested that SMAC mimetics may activate T cells, thereby promoting anti-tumor immunity. Here, we tested the effect of three clinically relevant SMAC mimetics on activation of primary human T cells. As previously reported, SMAC mimetics killed tumor cells and activated non-canonical NF-κB in T cells at clinically relevant doses. Surprisingly, none of the SMAC mimetics augmented T cell responses. Rather, SMAC mimetics impaired T cell proliferation and decreased the proportion of IFNγ/TNFα double-producing T cells. These results question the assumption that SMAC mimetics are likely to boost anti-tumor immunity in cancer patients.
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Caspasas , Neoplasias , Humanos , Caspasas/farmacología , Caspasas/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/farmacología , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Citocinas , Neoplasias/tratamiento farmacológico , Apoptosis , Mitocondrias/metabolismo , Proliferación Celular , Proteínas Mitocondriales/metabolismo , Línea Celular TumoralRESUMEN
OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening autoimmune diseases. Inhibitors of apoptosis proteins (IAPs) are a class of molecules engaged in cell death and inflammation, interventions of which are proven effective in a number of inflammatory diseases. Here we tested whether targeting IAPs could ameliorate AAV and explored the potential mechanism. METHODS: We collected 19 kidney specimens from patients with myeloperoxidase (MPO)-AAV to investigate the expression of IAPs. The IAP pan-inhibitor SM164 was used to treat the experimental autoimmune vasculitis (EAV) rat model of AAV. RNA sequencing of renal cortex and enrichment analysis were developed to interpret gene expression. Functional experiments were performed to investigate the role of SM164 on neutrophils and endothelial cells. RESULTS: The expression of three IAPs (cIAP1, cIAP2 and XIAP) was upregulated in kidneys of AAV patients compared with normal controls. SM164 dramatically reduced renal injury in EAV rats. Transcriptomic analysis revealed prominent alterations in fatty acid oxidation and respiratory burst following SM164 treatment. Functional studies demonstrated that SM164 inhibited neutrophil activation induced by MPO-ANCA positive IgG or serum from MPO-AAV patients, and such inhibitory effect was abolished by gene silencing or pharmacological inhibition of fatty acid oxidation. SM164 also inhibited the adhesion of neutrophils to endothelial cells with little effect on the endothelial injury induced by serum from MPO-AAV patients. CONCLUSION: Inhibition of IAPs with SM164 played a protective role in AAV through enhancing intracellular fatty acid oxidation in neutrophils.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Ratas , Animales , Peroxidasa , Células Endoteliales/metabolismo , Neutrófilos/metabolismo , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Ácidos GrasosRESUMEN
Survivin has received attention as a potential target for cancer immunotherapy because of its crucial role in oncogenesis. We undertook this study to evaluate the immunotherapeutic potential of combination of recombinant survivin along with adjuvant alum and immune modulator Mycobacterium indicus pranii (MIP). In vivo efficacy of the combination was studied in an invasive murine breast cancer model. Recombinant survivin protein was purified from Escherichia coli based expression system and characterized by western blotting. Purified survivin protein was combined with alum and MIP and was used for immunization of Balb/c mice. Antigen-primed animals were then challenged with syngeneic mammary tumor cells known as 4T-1. Balb/c mice spontaneously develop tumor when inoculated with 4T-1 cells. Antigen and adjuvant combination was immunogenic and significantly suppressed tumor growth in mice immunized with combination of recombinant survivin (10 µg), alum, and MIP. This is the first report that describes a combination immunotherapy approach using recombinant survivin, alum, and MIP in highly metastatic murine breast cancer model and holds promise for development of new biotherapeutics for cancer.
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Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/uso terapéutico , Neoplasias de la Mama/prevención & control , Vacunas contra el Cáncer/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Proteínas Represoras/uso terapéutico , Animales , Neoplasias de la Mama/patología , Modelos Animales de Enfermedad , Femenino , Inmunización , Inmunoterapia , Ratones Endogámicos BALB C , Proteínas Recombinantes/uso terapéutico , SurvivinRESUMEN
Although gene therapy has brought new insights into the treatment of malignant melanoma, targeting delivery of nucleic acid which targets critical oncogene/anti-oncogene in vivo is still a bottleneck in the therapeutic application. Our previous in vitro studies have found that the oncogene Livin could serve as a potential molecular target by small interfering RNA for gene therapy of malignant melanoma. However, how to transport Livin small interfering RNA into malignant melanoma cells specifically and efficiently in vivo needs further investigation. Cumulative evidence has suggested that single-chain antibody-mediated small interfering RNA targeted delivery is an effective way to silence specific genes in human cancer cells. Indeed, this study designed a protamine-single-chain antibody fusion protein, anti-MM scFv-tP, to deliver Livin small interfering RNA into LiBr cells. Further experiments confirmed the induction of cell apoptosis and suppression of cell proliferation by anti-MM scFv-tP in LiBr cells, along with efficient silence of Livin gene both in vitro and in vivo. Altogether, our findings provide a feasible approach to transport Livin small interfering RNA to malignant melanoma cells which would be a new therapeutic strategy for combating malignant melanoma.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/genética , Proteínas Inhibidoras de la Apoptosis/genética , Melanoma/terapia , Terapia Molecular Dirigida , Proteínas de Neoplasias/genética , ARN Interferente Pequeño/uso terapéutico , Proteínas Adaptadoras Transductoras de Señales/uso terapéutico , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Terapia Genética , Humanos , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Melanoma/genética , Melanoma/patología , Ratones , Proteínas de Neoplasias/uso terapéutico , ARN Interferente Pequeño/genética , Anticuerpos de Cadena Única/genética , Anticuerpos de Cadena Única/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In the last decade, significant progress has been made in understanding skin cancer cell death resistance mechanisms, and a number of new treatment strategies have been developed. Systematic approach genomic studies of various cancer types have opened new possibilities for the development of anticancer therapies. However, there are still fundamental gaps in the challenging biomedical puzzle, which will form a complete picture for curing cancer. Thus, herein, we describe some of the current cancer treatment strategies and discuss additional cell signalling pathways that could be potential targets for skin cancer treatment.
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Muerte Celular , Proliferación Celular , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal , Neoplasias Cutáneas/tratamiento farmacológico , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/antagonistas & inhibidores , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Sistema de Señalización de MAP Quinasas , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Neoplasias Cutáneas/fisiopatologíaRESUMEN
Neuronal death is the primary cause of vision loss in most retinal diseases. Neuroprotection is the modification of neurons, and/or their surrounding environment, to promote the survival and function of the neurons, especially in environments that would normally be deleterious to their health. Through advances in antioxidative therapy, neurotrophic support and anti-apoptotic therapy, the field of neuroprotection is advancing with the therapeutic hope of improving vision and clinical outcomes for patients.
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Neuroprotección/fisiología , Enfermedades de la Retina/prevención & control , Neuronas Retinianas/fisiología , Antioxidantes/uso terapéutico , Apoptosis , Supervivencia Celular/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Factores de Crecimiento Nervioso/uso terapéutico , Enfermedades de la Retina/fisiopatologíaRESUMEN
Magnetic albumin immuno-nanospheres (MAINs), simultaneously loaded with super-paramagnetic iron oxide nanoparticles for targeting application and anticancer gene, plasmid-survivin/shRNA (pshRNA) and modified with anti-EGFR monoclonal antibody Cetuximab for targeting and treatment agents, were prepared for targeting lung cancer. Transmission electron microscopy images and transfection photographs, respectively, showed that magnetic nanoparticles and pshRNA were successfully encased in the albumin nanospheres. The release profiles in vitro indicated that nanospheres had an obvious effect of sustained release of pshRNA. The results of slide agglutination test and immunofluorescence analysis demonstrated that the immuno-nanospheres retained the immuno-reactivity of Cetuximab. The MAINs significantly increased adherence and uptake by GLC-82 lung cancer cells over-expressed epidermal growth factor receptor over a magnetic albumin nanospheres (MANs) control. The pshRNA-loaded MAINs formulation was more effective than equimolar doses of free Cetuximab, single magnetic targeting with pshRNA (pshRNA-loaded MANs) or single monoclonal antibody targeting with pshRNA (pshRNA-loaded AINs) in the treatment of GLC-82 lung cancer cells. Collectively, the study indicates that the novel pshRNA-loaded magnetic immuno-nanospheres represent a promising approach for magnetic and monoclonal antibody-dependent gene targeting in lung cancer therapy.
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Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Nanopartículas de Magnetita/química , Nanosferas/química , ARN Interferente Pequeño/administración & dosificación , Albúmina Sérica Bovina/administración & dosificación , Transfección/métodos , Línea Celular Tumoral , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Receptores ErbB/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Nanopartículas de Magnetita/administración & dosificación , Nanopartículas de Magnetita/ultraestructura , Nanosferas/administración & dosificación , Nanosferas/metabolismo , Nanosferas/ultraestructura , Plásmidos/administración & dosificación , ARN Interferente Pequeño/química , ARN Interferente Pequeño/uso terapéutico , SurvivinRESUMEN
Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/uso terapéutico , Proteínas Mitocondriales/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Reguladoras de la Apoptosis , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Biomimética , Ensayos Clínicos como Asunto , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Neoplasias/patología , Neoplasias/radioterapia , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/uso terapéutico , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/uso terapéuticoRESUMEN
Histiocytic sarcoma (HS) in dogs exhibits aggressive biological behaviors and currently few effective treatments are available. Survivin could serve as a potential therapeutic target in several cancers. Sepantronium bromide (YM155) is a potential novel survivin-targeting agent and in this study the influence of survivin expression on clinical outcomes and the effects of YM155 on biological activities in HS cells were investigated. Specimens of HS dogs (n = 30) and four canine HS cell lines were used. The correlation between survivin expression and clinical outcome in the HS dogs was retrospectively assessed using quantitative PCR. Following YM155 treatment of cell lines, apoptosis, cell viability, and drug transporter activities were evaluated using annexin V staining, methylthiazole tetrazolium assays, and Hoechst-33342 staining, respectively. Elevated survivin expression in the HS dogs corresponded with reduced disease-free intervals and survival time, and increased chemoresistance, which led to poor clinical outcomes. Furthermore, YM155 treatment suppressed cell-growth and resistance to lomustine in HS cells by inhibiting the activity of ATP-binding cassette transporters. The evidence presented here supports favorable preclinical evaluation and indicates that survivin-targeted therapies might be effective against HS dogs.
Asunto(s)
Enfermedades de los Perros/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Sarcoma Histiocítico/veterinaria , Imidazoles/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Naftoquinonas/uso terapéutico , Animales , Antineoplásicos Alquilantes/uso terapéutico , Línea Celular Tumoral , Perros , Femenino , Sarcoma Histiocítico/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Lomustina/uso terapéutico , MasculinoRESUMEN
Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC-based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5×10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine.
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Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer , Células Dendríticas , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Antígeno Prostático Específico/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Vacunación , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias , Antineoplásicos/farmacología , Docetaxel , Humanos , Hipersensibilidad Tardía/inmunología , Proteínas Inhibidoras de la Apoptosis/farmacología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias , Antígeno Prostático Específico/farmacología , Neoplasias de la Próstata/inmunología , Survivin , Taxoides/farmacología , Taxoides/uso terapéuticoRESUMEN
PURPOSE: Alzheimer's disease (AD) is one of the untreatable neurodegenerative diseases characterised by the pathologic amyloid plaque deposition and inflammation. The aim of this study is to evaluate the neuroprotective effects of nanoformulated SurR9-C84A, a survivin mutant belonging to the inhibitors of the apoptosis (IAP) protein family. The effect of SurR9-C84A was studied against the ß-amyloid toxicity and various inflammatory insults in the differentiated SK-N-SH neurons. METHOD: SurR9-C84A loaded poly(lactic-co-glycolic acid) nanoparticles were prepared following the modified double emulsion technique. The neuroprotective effect of SurR9-C84A was evaluated against the amyloid-ß (Aß) peptide fragment, N-methyl-D-aspartate (NMDA) toxicity and the inflammatory assaults. To mimic the in vivo situation, a co-culture of neurons and microglia was also studied to validate these results. RESULTS: SurR9-C84A treatments showed improved neuronal health following Aß, and NMDA toxicity in addition to inflammatory insults induced in mono and co-cultures. The neuroprotective effect was evident with the reduced neuronal death, accelerated expression of neuronal integrity markers (neurofilaments, beta-tubulin III etc.,) and the neuroprotective ERK/MAPK signalling. CONCLUSION: The current results demonstrated that the SurR9-C84A nanoformulation was very effective in rescuing the neurons and holds a potential future application against AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular , Química Farmacéutica , Técnicas de Cocultivo , Citocinas/metabolismo , Humanos , Inflamación/inducido químicamente , Ácido Láctico , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Microglía/efectos de los fármacos , Nanopartículas , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , SurvivinRESUMEN
AIM: To determine the internalization and protective effects of potential ophthalmic formulations and nanoformulated natural proteins in ex-vivo bovine corneal alkali burn model. METHODS: The bovine cornea obtained were subjected to the 0.5N NaOH insult that induced alkali burn and inflammation as observed in the in vivo situation. The toxic effects of the nanoformulation were evaluated in the normal and insult induced cornea using histological analysis. Internalization studies were carried out using in vivo imaging and analysis (IVIS, PerkinElmer, USA). RESULTS: The nanoformulations employed in this study showed no obvious changes in the integrity of the cornea. Further, improvements in the light transmittance and reduced inflammation were observed. The IVIS showed a dose dependant increase in the uptake of the nanoformulations with time. CONCLUSION: The nanoformulated bovine lactoferrin and SurR9-C84A (SR9) proteins evaluated in the ex vivo bovine corneal irritation model is the first of its kind, and we report here the non-toxic and therapeutic potential of these formulations for topical applications.
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Quemaduras Químicas/tratamiento farmacológico , Quemaduras Oculares/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Lactoferrina/uso terapéutico , Nanopartículas/uso terapéutico , Animales , Bovinos , Quitosano/química , Quitosano/uso terapéutico , Córnea/efectos de los fármacos , Quemaduras Oculares/inducido químicamente , Proteínas Inhibidoras de la Apoptosis/química , Ácido Láctico/química , Ácido Láctico/uso terapéutico , Lactoferrina/química , Nanopartículas/química , Ácido Poliglicólico/química , Ácido Poliglicólico/uso terapéutico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Hidróxido de SodioRESUMEN
Benzo[a]pyrene (BaP), a component of cooking oil fumes (COF), promotes lung cancer cell proliferation and survival via the induction of inhibitor of apoptosis protein-2 (IAP-2) proteins. Thus knockdown of IAP-2 would be a promising way to battle against lung cancer caused by COF. Functionalized gold nanoparticle (AuNP) is an effective delivery system for bio-active materials. Here, biocompatible hyaluronic acid (HA) was fabricated into nanoparticles to increase the target specificity by binding to CD44-over-expressed cancer cells. IAP-2-specific small-interfering RNA (siRNAs) or fluorescein isothiocyanate (FITC) were then incorporated into AuNP-HA. Conjugation of IAP-2 siRNA into AuNPs-HA was verified by the UV-vis spectrometer and Fourier transform infrared spectrometer. Further studies showed that AuNP-HA/FITC were effectively taken up by A549 cells through CD44-mediated endocytosis. Incubation of BaP-challenged cells with AuNP-HA-IAP-2 siRNAs silenced the expression of IAP-2, decreased cell proliferation and triggered pronounced cell apoptosis by the decrease in Bcl-2 protein and the increase in Bax protein as well as the active form of caspases-3. The BaP-elicited cell migration and enzymatic activity of the secreted matrix metalloproteinase-2 were also substantially suppressed by treatment with AuNP-HA-IAP-2 siRNAs. These results indicated that IAP-2 siRNAs can be efficiently delivered into A549 cells by functionalized AuNP-HA to repress the IAP-2 expression and BaP-induced oncogenic events, suggesting the potential therapeutic application of IAP-2 siRNA or other siRNA-conjugated AuNP-HA composites to COF-induced lung cancer and other gene-caused diseases in the future.
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Sistemas de Liberación de Medicamentos/instrumentación , Oro/química , Ácido Hialurónico/química , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , Benzo(a)pireno/toxicidad , Materiales Biocompatibles , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Receptores de Hialuranos , Proteínas Inhibidoras de la Apoptosis/administración & dosificación , Neoplasias Pulmonares/inducido químicamente , Nanopartículas/química , ARN Interferente Pequeño/administración & dosificación , Especies Reactivas de OxígenoRESUMEN
PURPOSE: LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation. PATIENTS AND METHODS: LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control-guided dose escalation. RESULTS: Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels. CONCLUSION: The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.
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Antineoplásicos/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Neoplasias/tratamiento farmacológico , Tiazoles/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Citocinas/metabolismo , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/efectos adversos , Proteínas Inhibidoras de la Apoptosis/farmacocinética , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/metabolismo , Neoplasias/patología , Soluciones Farmacéuticas , Síndrome , Comprimidos , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
PURPOSE: To determine whether renal injury induced by ischemia-reperfusion (I/R) could be further improved by mesenchymal stem cells (MSCs) modified with survivin. MATERIALS AND METHODS: Lentiviral vectors were used to introduce the survivin gene into MSCs and the MSCs modified with survivin were transplanted into established mice models of renal I/R injury. Seven days later, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured and the survival of MSCs was determined. Hematoxylin and eosin staining was used to assess renal pathological change. The expressions of hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) in kidney tissue were detected by western blot. RESULTS: Mice transplanted with survivin-modified MSCs demonstrated good renal function recovery with Scr and BUN decline close to normal levels and improvement of renal I/R injury repair. Additionally, the survival of transplanted MSCs modified with survivin was enhanced and the expression of HGF and bFGF in kidney tissue was increased. CONCLUSION: Our results demonstrated that MSCs engineered to over-express survivin could enhance their therapeutic effect on renal I/R injury in mice, probably via the improved survival ability of MSCs and increased production of protective cytokines in ischemic tissue.
Asunto(s)
Células de la Médula Ósea/citología , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Trasplante de Células Madre Mesenquimatosas/métodos , Daño por Reperfusión/terapia , Proteínas Represoras/uso terapéutico , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/tratamiento farmacológico , SurvivinRESUMEN
Immune-based anti-tumor or anti-angiogenic therapies hold considerable promise for the treatment of cancer. The first approach seeks to activate tumor antigen-specific T lymphocytes while, the second, delays tumor growth by interfering with blood supply. Tumor Associated Antigens are often employed to target tumors with therapeutic drugs, but some are also essential for tumor viability. Survivin (Surv) is a member of the inhibitor of apoptosis protein family that is considered a Tumor Associated Antigen important for cancer cell viability and proliferation. On the other hand, Trypanosoma cruzi (the agent of Chagas' disease) calreticulin (TcCRT) displays remarkable anti-angiogenic properties. Because these molecules are associated with different tumor targets, we reasoned that immunization with a Surv-encoding plasmid (pSurv) and concomitant TcCRT administration should generate a stronger anti-tumor response than application of either treatment separately. To evaluate this possibility, C57BL/6 mice were immunized with pSurv and challenged with an isogenic melanoma cell line that had been pre-incubated with recombinant TcCRT (rTcCRT). Following tumor cell inoculation, mice were injected with additional doses of rTcCRT. For the combined regimen we observed in mice that: i). Tumor growth was impaired, ii). Humoral anti-rTcCRT immunity was induced and, iii). In vitro rTcCRT bound to melanocytes, thereby promoting the incorporation of human C1q and subsequent macrophage phagocytosis of tumor cells. These observations are interpreted to reflect the consequence of the following sequence of events: rTcCRT anti-angiogenic activity leads to stress in tumor cells. Murine CRT is then translocated to the external membrane where, together with rTcCRT, complement C1 is captured, thus promoting tumor phagocytosis. Presentation of the Tumor Associated Antigen Surv induces the adaptive anti-tumor immunity and, independently, mediates anti-endothelial cell immunity leading to an important delay in tumor growth.
Asunto(s)
Calreticulina/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Melanoma/tratamiento farmacológico , Trypanosoma cruzi/metabolismo , Animales , Calreticulina/administración & dosificación , Calreticulina/química , Calreticulina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complemento C1q/metabolismo , Femenino , Humanos , Inmunidad Humoral/efectos de los fármacos , Inmunización , Proteínas Inhibidoras de la Apoptosis/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanocitos/patología , Melanoma/irrigación sanguínea , Melanoma/inmunología , Melanoma/patología , Ratones Endogámicos C57BL , Modelos Biológicos , Neovascularización Patológica/terapia , Fagocitosis/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/patología , SurvivinRESUMEN
PURPOSE: To determine whether renal injury induced by ischemia-reperfusion (I/R) could be further improved by mesenchymal stem cells (MSCs) modified with survivin. MATERIALS AND METHODS: Lentiviral vectors were used to introduce the survivin gene into MSCs and the MSCs modified with survivin were transplanted into established mice models of renal I/R injury. Seven days later, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured and the survival of MSCs was determined. Hematoxylin and eosin staining was used to assess renal pathological change. The expressions of hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) in kidney tissue were detected by western blot. RESULTS: Mice transplanted with survivin-modified MSCs demonstrated good renal function recovery with Scr and BUN decline close to normal levels and improvement of renal I/R injury repair. Additionally, the survival of transplanted MSCs modified with survivin was enhanced and the expression of HGF and bFGF in kidney tissue was increased. CONCLUSION: Our results demonstrated that MSCs engineered to over-express survivin could enhance their therapeutic effect on renal I/R injury in mice, probably via the improved survival ability of MSCs and increased production of protective cytokines in ischemic tissue.