RESUMO
G-quadruplex structures within the nuclear genome (nG4) is an important regulatory factor, while the function of G4 in the mitochondrial genome (mtG4) still needs to be explored, especially in human sperms. To gain a better understanding of the relationship between mtG4 and mitochondrial function, it is crucial to develop excellent probes that can selectively visualize and track mtG4 in both somatic cells and sperms. Herein, based on our previous research on purine frameworks, we attempted for the first time to extend the conjugated structure from the C-8 site of purine skeleton and discovered that the purine derivative modified by the C-8 aldehyde group is an ideal platform for constructing near-infrared probes with extremely large Stokes shift (>220 nm). Compared with the compound substituted with methylpyridine (PAP), the molecule substituted with methylthiazole orange (PATO) showed better G4 recognition ability, including longer emission (â¼720 nm), more significant fluorescent enhancement (â¼67-fold), lower background, and excellent photostability. PATO exhibited a sensitive response to mtG4 variation in both somatic cells and human sperms. Most importantly, PATO helped us to discover that mtG4 was significantly increased in cells with mitochondrial respiratory chain damage caused by complex I inhibitors (6-OHDA and rotenone), as well as in human sperms that suffer from oxidative stress. Altogether, our study not only provides a novel ideal molecular platform for constructing high-performance probes but also develops an effective tool for studying the relationship between mtG4 and mitochondrial function in both somatic cells and human sperms.
Assuntos
Corantes Fluorescentes , Purinas , Humanos , Purinas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Doenças Mitocondriais/metabolismo , Regulação para Cima , Genoma Mitocondrial , Quadruplex G , Mitocôndrias/metabolismo , Raios Infravermelhos , Células HeLaRESUMO
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3.52 µM and 178.3 nM, respectively. In vitro cell-based assays revealed that 16 has no effect on the growth of various types of cancer cells, but has the potential to inhibit cancer cell migration and invasion. Western blotting analyses revealed that 16 suppresses the phosphorylation of focal adhesion kinase (FAK), a downstream molecule of MELK, which is a key kinase in regulating cancer cell migration and invasion.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Humanos , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacosRESUMO
Plant lectins have been investigated to elucidate their complicated mechanisms due to their remarkable anticancer activities. Although plant lectins seems promising as a potential anticancer agent for further preclinical and clinical uses, further research is still urgently needed and should include more focus on molecular mechanisms. Herein, a Naïve Bayesian model was developed to predict the protein-protein interaction (PPI), and thus construct the global human PPI network. Moreover, multiple sources of biological data, such as smallest shared biological process (SSBP), domain-domain interaction (DDI), gene co-expression profiles and cross-species interolog mapping were integrated to build the core apoptotic PPI network. In addition, we further modified it into a plant lectin-induced apoptotic cell death context. Then, we identified 22 apoptotic hub proteins in mesothelioma cells according to their different microarray expressions. Subsequently, we used combinational methods to predict microRNAs (miRNAs) which could negatively regulate the abovementioned hub proteins. Together, we demonstrated the ability of our Naïve Bayesian model-based network for identifying novel plant lectin-treated cancer cell apoptotic pathways. These findings may provide new clues concerning plant lectins as potential apoptotic inducers for cancer drug discovery.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias/metabolismo , Lectinas de Plantas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional , Bases de Dados de Proteínas , Descoberta de Drogas , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , MicroRNAs/genética , Modelos Biológicos , Neoplasias/genética , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Interferência de RNA , RNA Mensageiro/genéticaRESUMO
Lectins, a group of highly diverse proteins of non-immune origin and are ubiquitously distributed in plants, animals and fungi, have multiple significant biological functions, such as anti-fungal, anti-viral and, most notably, anti-tumor activities. A lectin was purified from the rhizomes of Aspidistra elatior Blume, named A. elatior lectin (AEL). In vitro experiments showed that the minimum inhibitory concentrations of AEL against the vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus were all the same at about 4 µg/mL. However, AEL was ineffective against the Sindbis virus and reovirus-1. AEL also showed significant in vitro antiproliferative activity towards Bre-04, Lu-04, HepG2, and Pro-01 tumor cell lines by increasing the proportion of their sub-G1 phase. However, AEL failed to restrict the proliferation of the HeLa cell line. Western blotting indicated that AEL induced the upregulation of cell cycle-related proteins p53 and p21. The molecular basis and species-specific effectiveness of the anti-proliferative and anti-viral potential of AEL are discussed.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antivirais/farmacologia , Liliaceae , Extratos Vegetais/farmacologia , Lectinas de Plantas/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antivirais/isolamento & purificação , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Células HeLa , Células Hep G2 , Humanos , Liliaceae/química , Testes de Sensibilidade Microbiana , Neoplasias/metabolismo , Neoplasias/patologia , Fitoterapia , Extratos Vegetais/isolamento & purificação , Lectinas de Plantas/isolamento & purificação , Plantas Medicinais , Rizoma , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo , Vírus/efeitos dos fármacos , Vírus/crescimento & desenvolvimentoRESUMO
Green tea catechins have been extensively studied for their cancer preventive effects. Accumulating evidence has shown that green tea catechins, like (-)-epigallocatechin-3-gallate, have strong anti-oxidant activity and affect several signal transduction pathways relevant to cancer development. Here, we review the biological properties of green tea catechins and the molecular mechanisms of their anticancer effects, including the suppression of cancer cell proliferation, induction of apoptosis, and inhibition of tumor metastasis and angiogenesis. We summarize the efficacy of a single catechin and the synergetic effects of multiple catechins. We also discuss the enhanced anticancer effects of green tea catechins when they are combined with anticancer drugs. The information present in this review might promote the development of strategy for the co-administration of green tea catechins with other anticancer drugs to increase the potency of currently available anticancer medicine. This new strategy should in turn lower the cytotoxicity and cost of anticancer treatment.
Assuntos
Antineoplásicos/administração & dosagem , Camellia sinensis/química , Catequina/administração & dosagem , Neoplasias/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologiaRESUMO
AIM: Proteins with legume lectin domains are known to possess a wide range of biological functions. Here, the antitumor effects of two representative legume lectins, concanavalin A (ConA) and Sophora flavescens lectin (SFL), on human breast carcinoma cells were investigated in vitro and in vivo. METHODS: Human breast carcinoma MCF-7 cells and human normal mammary epithelial MCF-10A cells were examined. Cell viability was detected using WST-1 and CCK-8 assays. Cell apoptosis was analyzed with Hoechst 33258 staining. Cell cycle was investigated using flow cytometry. The expression of relevant proteins was measured using Western blotting. Breast carcinoma MCF-7 bearing nude mice were used to study the antitumor effects in vivo. The mice were injected with ConA (40 mg/kg, ip) and SFL (55 mg/kg, ip) daily for 14 d. RESULTS: ConA and SFL inhibited the growth of MCF-7 cells in dose- and time-dependent manners (IC50 values were 15 and 20 µg/mL, respectively). Both ConA and SFL induced apoptotic morphology in MCF-7 cells without affecting MCF-10A cells. ConA and SFL dose-dependently increased the sub-G1 proportion in MCF-7 cells, while SFL also triggered the G2/M phase cell cycle arrest. Both ConA and SFL dose-dependently increased the activities of caspase-3 and caspase-9 and release of cytochrome C from mitochondria into cytoplasm, up-regulated Bax and Bid, and down-regulated Bcl-2 and Bcl-XL in MCF-7 cells. ConA reduced NF-κB, ERK, and JNK levels, and increased p53 and p21 levels, while SFL caused similar changes in NF-κB, ERK, p53, and p21 levels, but did not affect JNK expression. Administration of ConA and SFL significantly decreased the subcutaneous tumor mass volume and weight in MCF-7 bearing nude mice. CONCLUSION: ConA and SFL exert anti-tumor actions against human breast carcinoma MCF-7 cells both in vitro and in vivo.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Concanavalina A/farmacologia , Lectinas de Plantas/farmacologia , Sophora/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7RESUMO
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is becoming another "SARS-like" threat to the world. It has an extremely high death rate (â¼50%) as there is no vaccine or efficient therapeutics. The identification of the structures of both the MERS-CoV receptor binding domain (RBD) and its complex with dipeptidyl peptidase 4 (DPP4), raises the hope of alleviating this currently severe situation. In this review, we examined the molecular basis of the RBD-receptor interaction to outline why/how could we use MERS-CoV RBD to develop vaccines and antiviral drugs.
Assuntos
Antivirais/química , Infecções por Coronavirus/virologia , Coronavirus/imunologia , Dipeptidil Peptidase 4/imunologia , Desenho de Fármacos , Receptores Virais/imunologia , Vacinas Virais/química , Antivirais/uso terapêutico , Coronavirus/química , Coronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Humanos , Receptores Virais/química , Receptores Virais/metabolismoRESUMO
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of ß-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced ß-cell proliferation. For this purpose, adult C57BL/6J mice after 7-14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced ß-cell hyperplasia, elevated ß-cell proliferation and reduced ß-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to ß-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates ß-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes.
Assuntos
Células Secretoras de Insulina/citologia , Regeneração/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Xantonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina D2/genética , Ciclina D2/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Glucose/metabolismo , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Ilhotas Pancreáticas/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins widespread among monocotyledonous plants, is well-known to possess a broad range of biological functions such as anti-tumor, anti-viral and anti-fungal activities. Herein, we mainly focused on exploring the precise molecular mechanisms by which GNA-related lectins induce cancer cell apoptotic and autophagic death targeting mitochondria-mediated ROS-p38-p53 apoptotic or autophagic pathway, Ras-Raf and PI3K-Akt anti-apoptotic or anti-autophagic pathways. In addition, we further discussed the molecular mechanisms of GNA-related lectins exerting anti-viral activities by blocking the entry of the virus into its target cells, preventing transmission of the virus as well as forcing virus to delete glycan in its envelope protein and triggering neutralizing antibody. In conclusion, these findings may provide a new perspective of GNA-related lectins as potential drugs for cancer and virus therapeutics in the future.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antivirais/farmacologia , Galanthus/química , Lectinas de Plantas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antivirais/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Humanos , Lectinas de Plantas/química , Fenômenos Fisiológicos Virais/efeitos dos fármacosRESUMO
Autophagy, an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been implicated in diverse diseases including cancer. Autophagy can function as either a promoter or a suppressor of cancer, which makes it a promising and challenging therapeutic target. Herein, we overview the regulatory mechanisms and dual roles of autophagy in cancer. We also describe some of the representative agents that exert their anticancer effects by regulating autophagy. Additionally, some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery. In summary, these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Humanos , MicroRNAs/genética , Neoplasias/genética , Neoplasias/metabolismoRESUMO
Microautophagy, the non-selective lysosomal degradative process, involves direct engulfment of cytoplasmic cargo at a boundary membrane by autophagic tubes, which mediate both invagination and vesicle scission into the lumen. With its constitutive characteristics, microautophagy of soluble substrates can be induced by nitrogen starvation or rapamycin via regulatory signaling complex pathways. The maintenance of organellar size, membrane homeostasis, and cell survival under nitrogen restriction are the main functions of microautophagy. In addition, microautophagy is coordinated with and complements macroautophagy, chaperone-mediated autophagy, and other self-eating pathways. Three forms of selective microautophagy, including micropexophagy, piecemeal microautophagy of the nucleus, and micromitophagy, share common ground with microautophagy to some degree. As the accumulation of experimental data, the precise mechanisms that govern microautophagy are becoming more appreciated. Here, we review the microautophagic molecular machinery, its physiological functions, and relevance to human diseases, especially in diseases involving multivesicular bodies and multivesicular lysosomes.
Assuntos
Autofagia , Animais , Vesículas Citoplasmáticas/metabolismo , Homeostase , Humanos , Transdução de SinaisRESUMO
Autophagy, an evolutionarily conserved lysosomal degradation process, has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.
Assuntos
Autofagia , Descoberta de Drogas , Neoplasias/patologia , Antibióticos Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína Beclina-1 , Cloroquina/uso terapêutico , Humanos , Proteínas de Membrana/metabolismo , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/terapia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Parkinson's disease (PD) is one of the neurodegenerative diseases that is characterized by obvious motor and some nonmotor symptoms. Various therapeutics failed in the effective treatment of PD because of impaired neurological function in the brain and various complications. Periplaneta Americana oligosaccharides (OPA), the main active ingredients extracted from the medicine residues of Periplaneta Americana (P. Americana), have been reported to exert anti-inflammatory effects. The purpose of this study was to evaluate the possible mechanisms of OPA against 1-methyl-4-phenylpyridinium (MPP+)-induced apotosis in SH-SY5Y cells and its potential neuroprotective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD subacute model mice. The data demonstrated that OPA significantly reversed the MPP+-induced decrease in SH-SY5Y cell viability, reduced the proportion of apoptotic cells, and protected SH-SY5Y cells from apoptosis in a dose-dependent manner by regulating the expression of apoptosis-related genes. Furthermore, OPA also alleviated the motor dysfunction of PD model mice, prevented the loss of tyrosine hydroxylase positive cells, suppressed the apoptosis of substantia nigra cells, and improved the dysbiosis of gut microbiota in vivo, suggesting that OPA demonstrated a significantly neuroprotective effect on PD model mice. These results indicated that OPA might be the possibility of PD therapeutics with economic utility and high safety.
RESUMO
Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding plant lectin, has recently drawn a rising attention for cancer biologists because PCL bears remarkable anti-tumor activities and thus inducing programmed cell death (PCD) including apoptosis and autophagy in cancer cells. In this review, we focus on exploring the precise molecular mechanisms by which PCL induces cancer cell apoptotic death such as the caspase-dependent pathway, mitochondria-mediated ROS-p38-p53 pathway, Ras-Raf and PI3K-Akt pathways. In addition, we further elucidate that PCL induces cancer cell autophagic death via activating mitochondrial ROS-p38-p53 pathway, as well as via blocking Ras-Raf and PI3K-Akt pathways, suggesting an intricate relationship between autophagic and apoptotic death in PCL-induced cancer cells. In conclusion, these findings may provide a new perspective of Polygonatum cyrtonema lectin (PCL) as a potential anti-tumor drug targeting PCD pathways for future cancer therapeutics.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Lectinas de Plantas/farmacologia , Polygonatum/química , Sequência de Aminoácidos , Caspases/metabolismo , Linhagem Celular Tumoral , Humanos , Dados de Sequência Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Lectinas de Plantas/química , Conformação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismoRESUMO
Concanavalin A (ConA), a Ca(2+)/Mn(2+)-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-κB-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Concanavalina A/farmacologia , Neoplasias/tratamento farmacológico , Sequência de Aminoácidos , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Concanavalina A/química , Concanavalina A/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases , Dados de Sequência Molecular , Neoplasias/irrigação sanguínea , Neoplasias/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas ras/metabolismoRESUMO
INTRODUCTION: In many diseased states, especially fibrosis and cancer, TGF-ß family members are overexpressed and the outcome of signaling is diverted toward disease progression. As the result of activin receptor-like kinase 1 (ALK1) plays a key role in TGF-ß signaling, discovering inhibitors of ALK1 to block TGF-ß signaling for a therapeutic benefit has become an effective strategy. METHODS: In this work, ZINC15894217 and ZINC12404282 were identified as potential ALK1 inhibitors using molecular docking, molecular dynamics simulation and MM/PBSA calculations studies. The analysis of energy decomposition found that Val208, Val216, Lys229, Gly283, Arg334 and Leu337 acted as crucial residues for ligand binding and system stabilizing. RESULTS: In addition, these compounds displayed excellent pharmacological and structural properties, which can be further evaluated through in vitro and in vivo experiments for the inhibition of ALK1 to be developed as drugs against fibrosis and tumor. CONCLUSION: Overall, our study illustrated a time- and cost-effective computer aided drug design procedure to identify potential ALK1 inhibitors. It would provide useful information for further development of ALK1 inhibitors to improve disease related to TGF-ß signal pathway.
Assuntos
Neoplasias , Fator de Crescimento Transformador beta , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Transdução de SinaisRESUMO
BACKGROUND: The Galanthus nivalis agglutinin (GNA)-related lectins have been reported to bear antiproliferative and apoptosis-inducing activities in cancer cells; however, the precise mechanisms by which GNA-related lectins induce cell death are still only rudimentarily understood. METHODS: In the present study, Polygonatum odoratum lectin (designated POL), a mannose-binding specific GNA-related lectin, possessed a remarkable antiproliferative activity toward murine fibrosarcoma L929 cells. And, this lectin induced L929 cell apoptosis in a caspase-dependent manner. In addition, POL treatment increased the levels of FasL and Fas-Associated protein with Death Domain (FADD) proteins and resulted in caspase-8 activation. Also, POL treatment caused mitochondrial transmembrane potential collapse and cytochrome c release, leading to activations of caspase-9 and caspase-3. Moreover, POL treatment enhanced tumor necrosis factor alpha (TNFalpha)-induced L929 cell apoptosis. RESULTS: Our data demonstrate for the first time that this lectin induces apoptosis through both death-receptor and mitochondrial pathways, as well as amplifies TNFalpha-induced L929 cell apoptosis. GENERAL SIGNIFICANCE: These inspiring findings would provide new molecular basis for further understanding cell death mechanisms of the Galanthus nivalis agglutinin (GNA)-related lectins in future cancer investigations.
Assuntos
Apoptose/efeitos dos fármacos , Fibrossarcoma/patologia , Lectinas de Plantas/farmacologia , Polygonatum/metabolismo , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fibrossarcoma/enzimologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fitoterapia , Receptores de Morte Celular/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Autophagy is an evolutionarily conserved lysosomal self-digestion process involved in degradation of long-lived proteins and damaged organelles. In recent years, increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. In this review, we focus on the recent studies of the evolutionarily conserved autophagy-related genes (ATGs) that are implicated in autophagosome formation and the pathways involved. We discuss several key autophagic mediators (eg, Beclin-1, UVRAG, Bcl-2, Class III and I PI3K, mTOR, and p53) that play pivotal roles in autophagic signaling networks in cancer. We discuss the Janus roles of autophagy in cancer and highlighted their relationship to tumor suppression and tumor progression. We also present some examples of targeting ATGs and several protein kinases as anticancer strategy, and discuss some autophagy-modulating agents as antitumor agents. A better understanding of the relationship between autophagy and cancer would ultimately allow us to harness autophagic pathways as new targets for drug discovery in cancer therapeutics.
Assuntos
Antineoplásicos/farmacologia , Autofagia , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Neoplasias/metabolismoRESUMO
A number of multimodal agents have been developed for tumour imaging and diagnosis, but most of them cannot be used to study the detailed physiological or pathological changes in living cells at the same time. Herein, a series of pH-responsive magnetic resonance and fluorescence imaging (MRI/FI) dual-modal "nanovehicles" are developed and tested. These new dual-modal materials allow for intercellular pH sensing, and those with units that are dually sensitive towards both acidic and basic environments have the ability for intracellular pH mapping and can be used to quantify pH at the cellular level. In addition, detailed pH changes in organelles (including lysosomes and mitochondria) can be investigated at the same time. On the other hand, with the tumour-targeting peptide (cRGD)-modified dual-modal nanovehicles, in vivo tumour MR and fluorescence imaging, which is suitable for cancer diagnosis, can be achieved. Moreover, it has been proved that these materials can pass through the blood brain barrier (BBB). By combining the above mentioned promising properties, these novel multifunctional "nanovehicles" may provide a new method for studying the role of pH during cancer diagnosis and treatment.
Assuntos
Sistemas de Liberação de Medicamentos , Ouro , Imageamento por Ressonância Magnética , Nanopartículas Metálicas , Neoplasias Experimentais , Imagem Óptica , Animais , Feminino , Ouro/química , Ouro/farmacocinética , Ouro/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The objective of this study was to investigate the antiproliferative activity and apoptosis-inducing mechanism of Concanavalin A (ConA) on human melanoma A375 cells. We firstly simulated the three-dimensional structure of ConA. Subsequently, we found that ConA possessed remarkable antiproliferative effect on A375 cells. Further experimental data indicated that there was a link between its hemagglutinating activity, mannose-binding activity and antiproliferative activity. In addition, we showed that ConA induced A375 cell apoptosis in a caspase-dependent manner. Then, we demonstrated that the treatment of ConA caused mitochondrial transmembrane potential (MMP) collapse, cytochrome c release and caspase activation. In conclusion, we report for the first time that there may be a close correlation between carbohydrate-binding activity of ConA and its antiproliferative activity. Also, we demonstrate firstly that ConA induces A375 cell death in a caspase-dependent manner as well as through a mitochondrial apoptotic pathway.