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Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional therapies have limited efficacy, and relapses with high mortality rates are still frequent. Cordycepin, a nucleoside analog extracted from Cordyceps species, represents a wide range of therapeutic effects, including anti-inflammatory, anti-tumor, and anti-metastatic activities. Cordycepin induces apoptosis in different subtypes of HMs by triggering adenosine receptors, death receptors, and several vital signaling pathways such as MAPK, ERK, PI3K, AKT, and GSK-3ß/ß-catenin. This review article summarizes the impact of utilizing cordycepin on HMs, and highlights its potential as a promising avenue for future cancer research based on evidence from in vitro and in vivo studies, as well as clinical trials.
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Neoplasias Hematológicas , Humanos , Glucógeno Sintasa Quinasa 3 beta , Neoplasias Hematológicas/tratamiento farmacológico , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , ApoptosisRESUMEN
INTRODUCTION: T-cell acute lymphoblastic leukemia is characterized by its fast progression rate and high complications. TRAIL can be used to trigger apoptosis in cancer cells with minimal effects on normal cells, but most of cancer cells develop resistance to this agent through various mechanisms. HDAC inhibitors like SAHA can be used to make cancer cells more susceptible to TRAIL-induced apoptosis. In this study, this hypothesis was tested on MOLT-4 cancer cell line. MATERIALS AND METHODS: The cells were divided into six groups including the control group, TRAIL 50 nM, TRAIL 100 nM, SAHA 2 µM, SAHA 2 µM + TRAIL 50 nM, and SAHA 2 µM + TRAIL 100 nM. Apoptosis was evaluated by flowcytometry after 24, 48 and 72 h. The expression levels of c-flip, DR4, DR5, CHOP, NF-κB, STAT3, Akt, and PI3K genes were investigated by quantitative real-time PCR. Data were analyzed using two-way variance analysis with Tukey's and Dunnett's multiple comparisons tests, and statistical significance was defined as having a p-value less than 0.05. RESULTS: Groups exposed to the combination of SAHA with TRAIL demonstrated the maximum apoptosis in MOLT-4 cells by increasing the expression of DR4, DR5, and CHOP and decreasing the expression of c-flip, STAT3, PI3k, Akt, and NF-kB genes. CONCLUSION: It can be concluded that SAHA increases the sensitivity of MOLT-4 cells to TRAIL-mediated apoptosis, which can be used as a strategy to overcome resistance to TRAIL in leukemic patients.
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Neoplasias , Proteínas Proto-Oncogénicas c-akt , Humanos , Apoptosis , Línea Celular , Citometría de Flujo , FN-kappa B , Fosfatidilinositol 3-QuinasasRESUMEN
Exposure to numerous pollutants is prevalent in workplaces. Examination of combined exposure to different harmful physical factors and chemicals has offered new insights into toxicology in recent years. This study aimed to investigate the hematological alterations caused by exposure to noise and toluene. Twenty-four New Zealand white rabbits were exposed to 1000 ± 50 ppm toluene and/or 100 ± 5 dB noise for 14 consecutive days. Exposure to noise and toluene changed a number of parameters of white blood cells (WBC), red blood cells (RBC), and platelets on different days after the exposure. Simultaneous exposure to noise and toluene increased WBC, and exposure to noise and toluene alone decreased RBC. Exposure to noise and toluene alone increased basophile, monocyte, and neutrophil counts. The coefficient of variation of red blood cell distribution width (RDW-CV) and the standard deviation of red blood cell distribution width (RDW-SD) significantly increased after co-exposure to noise and toluene. Platelet levels increased in the noise-exposed and the co-exposed groups and decreased in the toluene-exposed group. Furthermore, co-exposure to noise and toluene induced dissimilar synergistic and antagonistic effects on the hematological indices. According to the results of this study, simultaneous exposure to toluene and noise can aggravate some hematotoxic effects compared to exposure to noise or toluene alone. The results also demonstrated the vital role of the modulatory mechanisms of the body in controlling the detrimental effects of stressors.
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Ruido , Tolueno , Conejos , Animales , Tolueno/toxicidadRESUMEN
BACKGROUND: However, advanced technologies have been developed in the treatment of various cancers, but the mortality rate from cancer is still very high. Drug resistance is a major problem for patients with cancer, which causes the treatment process to fail. In addition to inhibiting drug resistance, targeted therapy is also very important in treatment. MAIN BODY: Nowadays, miRNAs have gained increasing interest as they play a major role in both drug resistance and targeted therapy. MicroRNA (miRNA) is an important part of non-coding RNA that regulates gene expression at a post-transcriptional level. The prevailing studies about miRNA expression have been expanded into a variety of neoplasms. MiR-424 and miR-631 targets genes involved in various cellular processes and can participate in proliferation, differentiation, apoptosis, invasion, angiogenesis, and drug resistance and sensitivity. CONCLUSION: In this study, we focus on the role of miR-424 and miR-631 in many cancer types by displaying the potential target genes associated with each cancer, as well as briefly describing the clinical uses of miR-424 and miR-631 as a diagnostic and predictive tool in malignancies.
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MicroARNs , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , MicroARNs/genética , MicroARNs/metabolismo , Apoptosis , Resistencia a Medicamentos , Regulación Neoplásica de la Expresión Génica/genéticaRESUMEN
Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.
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Drug resistance is the drug-effectiveness reduction in treatment and is a serious problem in oncology and infections. In oncology, drug resistance is a complicated process resulting from enhancing the function of a pump that transports drugs out of tumor cells, or acquiring mutations in drug target. Surprisingly, most drugs are very effective in the early stages, but the response to the drug wears off over time and resistance eventually develops. Drug resistance is caused by genetic and epigenetic changes that affect cancer cells and the tumor environment. The study of inherited changes in the phenotype without changes in the DNA sequence is called epigenetics. Because of reversible changes in epigenetics, they are an attractive target for therapy. Some of these epigenetic drugs are effective in treating cancers like acute myeloid leukemia (AML), which is characterized by the accumulation and proliferation of immature hematopoietic cells in the blood and bone marrow. In this article, we outlined the various contributing factors involved in resistance or sensitivity to epigenetic drugs in the treatment of AML.
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Leucemia Mieloide Aguda , Médula Ósea/patología , Epigénesis Genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , MutaciónRESUMEN
BACKGROUND: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, an apoptosis-inducing cytokine, has attracted much attention in the treatment of cancer for its selective toxicity to malignant rather than normal cells. However, the apoptosis-inducing ability of TRAIL is weaker than expected primarily due to cancer cell resistance. As one of the dietary flavonoids, kaempferol, has been shown to be antiproliferative and might have a protective effect against TRAIL resistance, particularly for hematologic malignancies. METHODS AND RESULTS: Here, we studied the potential of kaempferol to enhance the TRAIL-induced cytotoxicity and apoptosis in human chronic myelogenous leukemia (CML) cell line K-562, as well as the expression of specific genes with impact on TRAIL signal regulation. Analysis of flowcytometry data showed that treatment with kaempferol did enhance sensitivity of CML cells to pro-apoptotic effects of anti-TRAIL antibody. Although the gene expression levels were heterogeneous, cFLIP, cIAP1 and cIAP2 expression were generally downregulated where co-treatment of kaempferol and TRAIL was employed and these effects appeared to be dose-dependent. We further demonstrated that the expression of death receptors 4 and 5 tended to increase subsequent to the combination treatment. CONCLUSIONS: Consequently, it is reasonable to conclude that sensitization of chronic leukemia cells to TRAIL by kaempferol in vitro should be considered as a way of focusing clinical attention on leukemia therapy.
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Proteínas Reguladoras de la Apoptosis/genética , Quempferoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Mesenchymal stem cells (MSCs) are one of the most prominent cells in the bone marrow. MSCs can affect acute lymphocytic leukemia (ALL) cells under hypoxic conditions. With this aim, we used MOLT-4 cells as simulators of ALL cells cocultured with bone marrow mesenchymal stem cells (BMMSCs) under hypoxic conditions in vitro. Then, mRNA and protein expression of the MAT2A, PDK1, and HK2 genes were evaluated by real-time PCR and Western blot which was also followed by apoptosis measurement by a flow-cytometric method. Next, the methylation status of the target genes was investigated by MS-qPCR. Additionally, candidate gene expressions were examined after treatment with rapamycin using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We found that the mRNA expression of the candidate genes was augmented under the hypoxic condition in which MAT2A was upregulated in cocultured cells compared to MOLT-4, while HK2 and PDK1 were downregulated. Moreover, we found an association between gene expression and promoter methylation levels of target genes. Besides, expressions of the candidate genes were decreased, while their methylation levels were promoted following treatment with rapamycin. Our results suggest an important role for the BMMSC in regulating the methylation of genes involved in cell survival in hypoxia conditions; however, we found no evidence to prove the MSCs' effect on directing malignant lymphoblastic cells to apoptosis.
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Células Madre Mesenquimatosas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Apoptosis/genética , Células de la Médula Ósea/metabolismo , Hipoxia de la Célula/genética , Humanos , Hipoxia/metabolismo , Células Madre Mesenquimatosas/metabolismo , Metionina Adenosiltransferasa , Metilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , ARN Mensajero/metabolismo , SirolimusRESUMEN
DNA methylation is a reversible biochemical process determinant of gene expression that is frequently observed in acute lymphoblastic leukemia (ALL). This is believed to arise from aberrant DNA methyltransferase activity establishing abnormal levels of DNA methylation in tumor cells. DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), is a clinically used epigenetic drug which induces promoter demethylation and gene re-expression in human cancers. In this study, we investigated the cytotoxicity of on MOLT4 and Jurkat leukemic cell line in vitro and characterized the underlying molecular mechanisms of cell death and motility. MOLT4 and Jurkat cells were treated with 5-AZA for 12, 24 and 48 hours. The effect of the 5-AZA treatment on cell viability (MTT assay), apoptosis (annexin V/PI staining), microRNA (miRNA) and mRNA expression (real-time PCR) was measured. The results showed that 5-AZA could induce MOLT4 and Jurkat apoptotic cell death in vitro in a time-dependent manner and probably via apoptotic mechanisms. We found that treatment with 5-AZA could increase the expression of epigenetically silenced miRNAs, miR-34a, miR-34b and miR-124-1 in treated cells. In addition, mRNA analyses demonstrated that MOLT4 and jurkat cells, expressed p53 gene more than 10-fold higher compared with untreated cells in three independent experiments while the cells suppressed the expression of a subset of functionally related genes including MYC, BCL2, APEX, SIRT1, SNAIL1 and vimentin to some extent, following 5-AZA treatment. We found that a miRNAs expression level in treated cell lines was closely correlated to the expression of their target genes. Together, these findings suggest that 5-AZA may affect the viability of MOLT4 and jurkat cells, at least in part, by regulating the transcription of genes that are associated with cellular apoptotic response.
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Azacitidina/farmacología , Muerte Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Humanos , MicroARNs/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to investigate the effect of mimic hypoxia on proliferation, the expression of significant miRNAs, and genes involved in drug resistance in MOLT-4 and KG1 cell lines. MATERIALS AND METHODS: The KG1 and MOLT-4 cell lines were cultured in RPMI 1640 medium supplemented with 20% FBS and 10% FBS respectively. The MTT test was used for determining the optimum dose of CoCl2 for KG1 and MOLT-4 cell lines. Western blotting was used for the detection of HIF-1a protein and the confirmation of mimic hypoxia induced by CoCl2. For evaluating the effect of mimic hypoxia on proliferation of MOLT-4 and KG1 cell lines, cell counting was done using trypan blue at 24, 48, and 72 hours. Furthermore, the results obtained from cell counting were confirmed with the MTT test. Total RNA was extracted using the RNX Plus solution kit according to the manufacturer's protocol. The expression of genes and miRNAs was evaluated with real time PCR. RESULTS: According to this study, mimic hypoxia induced by CoCl2 contributes to the overexpression of drug resistance related genes including MDR1, MRP1, FOXM1, BCL-xl genes, and the suppression of PUMA gene compared to the control group. The results also showed that mimic hypoxia condition leads to the up-regulation of miR-9 and down-regulation of miR-27a and miR-370. Additionally, our outcomes demonstrated that mimic hypoxia has an inhibitory effect on the proliferation of MOLT-4 and KG1 cell lines. CONCLUSION: Treatment with CoCl2 has an inhibitory effect on the proliferation of MOLT-4 and KG1 cell lines independent from real hypoxia. Additionally, mimic hypoxia has a substantial effect on the expression of genes and miRNAs involved in drug resistance. Finally, we are still far away to discover the exact functional mechanisms of hypoxia on drug resistance but these evaluations can provide new perspectives into this field for the upcoming studies.
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Hipoxia de la Célula , Cobalto/farmacología , MicroARNs/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Medicamentos/genética , HumanosRESUMEN
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Several environmental and genetic factors are known to be involved in its development and progression. The angiopoietin-Tie system is one of the most critical factors in angiogenesis, and its possible role in solid tumors and leukemia has been previously investigated. In this study, we examined the expression of these genes in ALL patients (early pre-B-ALL and pre-B-ALL) and compared them with normal samples. METHODS: Bone marrow samples were collected from 40 patients (aged 0â19 yr) newly diagnosed with early pre-B-ALL or pre-B-ALL using molecular and flow cytometric tests and from 15 control individuals. For molecular tests, RNA extraction and cDNA synthesis were performed, and Ang1, Ang2, Ang4, Tie1, and Tie2 gene expression was examined by real-time polymerase chain reaction. RESULTS: Ang2, Tie1, and Tie2 gene expression were significantly increased in patients with ALL, whereas Ang1 gene expression was decreased. The Ang4 gene did not show significant expression changes between the two groups. CONCLUSION: Changes in the expression of the Ang-Tie system indicate a possible role of angiogenesis in ALL prognosis. Moreover, such changes can be considered as potential diagnostic biomarkers or therapeutic targets.
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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications.
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Multiple factors, including growth factors, are shown to be culprits of cancer outset and persistence. Among growth factors, insulin-like growth factors (IGFs) family are of more importance in the prognosis of blood malignancies. After binding to their corresponding receptor, IGFs initiate PI3K/AKT signaling pathway and increase the translation of intracellular proteins, such as cell division-related proteins. They also stimulate the transcription of cell division-related genes using the Ras-GTP pathway. In addition to organs such as the liver, IGFs are secreted by tumor cells and can cause growth and proliferation of self or tumor cells via autocrine and paracrine methods. Current studies indicate that decreasing the effects of IGF by blocking them, their receptors, or PI3K/AKT pathway using various drugs could help to suppress the division of tumor cells. Here, we delineate the role of the IGF family in hematologic malignancies and their potential mechanisms.
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Neoplasias Hematológicas/metabolismo , Somatomedinas/metabolismo , Animales , Antineoplásicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Ligandos , Receptores de Somatomedina/metabolismo , Transducción de Señal , Somatomedinas/genética , Somatomedinas/uso terapéuticoRESUMEN
OBJECTIVE: Zoledronic Acid (ZA) is one of the common treatment choices used in various boneassociated conditions. Also, many studies have investigated the effect of ZA on Osteoblastic-Differentiation (OSD) of Mesenchymal Stem Cells (MSCs), but its clear molecular mechanism(s) has remained to be understood. It seems that the methylation of the promoter region of key genes might be an important factor involved in the regulation of genes responsible for OSD. The present study aimed to evaluate the changes in the mRNA expression and promoter methylation of central Transcription Factors (TFs) during OSD of MSCs under treatment with ZA. MATERIALS AND METHODS: MSCs were induced to be differentiated into the osteoblastic cell lineage using routine protocols. MSCs received ZA during OSD and then the methylation and mRNA expression levels of target genes were measured by Methylation Specific-quantitative Polymerase Chain Reaction (MS-qPCR) and real-time PCR, respectively. The osteoblastic differentiation was confirmed by Alizarin Red Staining and the related markers to this stage. RESULTS: Gene expression and promoter methylation level for DLX3, FRA1, ATF4, MSX2, C/EBPζ, and C/EBPa were up or down-regulated in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21. ATF4, DLX3, and FRA1 genes were significantly up-regulated during the OSD processes, while the result for MSX2, C/EBPζ, and C/EBPa was reverse. On the other hand, ATF4 and DLX3 methylation levels gradually reduced in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21, while the pattern was increasing for MSX2 and C/EBPa. The methylation pattern of C/EBPζ was upward in untreated groups while it had a downward pattern in ZA-treated groups at the same scheduled time. The result for FRA1 was not significant in both groups at the same scheduled time (days 0-21). CONCLUSION: The results indicated that promoter-hypomethylation of ATF4, DLX3, and FRA1 genes might be one of the mechanism(s) controlling their gene expression. Moreover, we found that promoter-hypermethylation led to the down-regulation of MSX2, C/EBP-ζ and C/EBP-α. The results implicate that ATF4, DLX3 and FRA1 may act as inducers of OSD while MSX2, C/EBP-ζ and C/EBP-α could act as the inhibitor ones. We also determined that promoter-methylation is an important process in the regulation of OSD. However, yet there was no significant difference in the promoter-methylation level of selected TFs in ZA-treated and control cells, a methylation- independent pathway might be involved in the regulation of target genes during OSD of MSCs.
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Enfermedades Óseas/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Ácido Zoledrónico/farmacología , Enfermedades Óseas/patología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Estructura Molecular , Osteogénesis/efectos de los fármacos , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/genética , ARN Mensajero/metabolismo , Relación Estructura-Actividad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ácido Zoledrónico/síntesis química , Ácido Zoledrónico/químicaRESUMEN
As cancers are one of the most important causes of human morbidity and mortality worldwide, researchers try to discover novel compounds and therapeutic approaches to decrease survival of cancer cells, angiogenesis, proliferation and metastasis. In the last decade, use of special phytochemical compounds and flavonoids was reported to be an interesting and hopeful tactic in the field of cancer therapy. Flavonoids are natural polyphenols found in plant, fruits, vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities. The main aim of this review is to evaluate the relationship between flavonoids consumption and cancer risk, and discuss the anti-cancer effects of these natural compounds in human cancer cells. Hence, we tried to collect and revise important recent in vivo and in vitro researches about the most effective flavonoids and their main mechanisms of action in various types of cancer cells.
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Antineoplásicos/farmacología , Flavonoides/farmacología , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Flavonoides/química , HumanosRESUMEN
MicroRNAs (miRNAs) characterized by small, noncoding RNAs have a fundamental role in the regulation of gene expression at the post-transcriptional level. Additionally, miRNAs have recently been identified as potential regulators of various genes involved in the pathogenesis of the autoimmune and inflammatory disease. So far, the interaction between miRNAs and T lymphocytes in the immune response as a new and significant topic has not been emphasized substantially. The role of miRNAs in different biological processes including apoptosis, immune checkpoints and the activation of immune cells is still unclear. Aberrant miRNA expression profile affects various aspects of T-cell function. Accordingly, in this literature review, we summarized the role of significant miRNAs in T-cell development processes. Consequently, we demonstrated precise mechanisms that candidate miRNAs interfere in Immune response mediated by different types of T cells. We believe that a good understanding of the interaction between miRNAs and immune response contributes to the new therapeutic strategies in relation to disease with an immunological origin.
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Diferenciación Celular/genética , Hemostasis/fisiología , Inmunidad/genética , Linfocitos T/inmunología , Animales , Apoptosis/genética , Humanos , MicroARNs/genéticaRESUMEN
Purpose: Sepantronium bromide (YM155) is a Survivin inhibitor which recently advanced as an anticancer agent in phase II clinical trials. Survivin belongs to IAP (inhibitor of apoptosis) gene family and is a pivotal target for treatment due to its overexpression and oncogenic function in many malignancies, including acute lymphoblastic leukemia (ALL). Although survivin is a specific target for YM155, recent reports have shown that it has many other crucial targets that regulate its anti-apoptotic effects. The aim of this study was to investigate whether YM155 could have an effect on cell death-inducing genes as well as inducing apoptosis in T-ALL MOLT4- cell line. Methods: We treated MOLT-4 cells with increasing concentrations of YM155 and then cell viability was determined using MTT (methyl thiazolyl tetrazolium) assay. Also, the rate of induction of apoptosis in MOLT-4 cells and the target genes expression levels were evaluated by Annexin V/PI and real-time PCR, respectively. Results: YM155 inhibited cell growth in MOLT-4 cells. This outcome is achieved by inducing apoptosis and a significant increase in the expression level of P53, MiR-9, caspase 3 and decreasing the mRNA expression levels of survivin, Sirtuin1(SIRT1), member of anti-apoptotic proteins family (Bcl-2), and epithelial-to-mesenchymal transition (EMT) initiating factors Snail1and Zeb2. Conclusion: The results showed that use of YM155 can be a potential drug therapy in T-ALL patients with promising effects on apoptosis induction.
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BACKGROUND: The Enhancer of Zeste Homolog 2 (EZH2) is a subunit of the polycomb repressive complex 2 that silences the gene transcription via H3K27me3. Previous studies have shown that EZH2 has an important role in the induction of the resistance against the Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis (TIA) in some leukemia cells. OBJECTIVE: The aim of this study was to determine the effect of silencing EZH2 gene expression using RNA interference on the expression of death receptors 4 and 5 (DR4/5), Preferentially expressed Antigen in Melanoma (PRAME), and TRAIL human lymphoid leukemia MOLT-4 cells. METHODS: Quantitative RT-PCR was used to detect the EZH2 expression and other candidate genes following the siRNA knockdown in MOLT-4 cells. The toxicity of the EZH2 siRNA was evaluated using Annexin V/PI assay following the transfection of the cells by 80 pM EZH2 siRNA at 48 hours. RESULTS: Based on the flow-cytometry results, the EZH2 siRNA had no toxic effects on MOLT-4 cells. Also, the EZH2 inhibition increased the expression of DR4/5 but reduced the PRAME gene expression at the mRNA levels. Moreover, the EZH2 silencing could not change the TRAIL mRNA in the transfected cells. CONCLUSION: Our results revealed that the down-regulation of EZH2 in MOLT-4 cells was able to affect the expression of important genes involved in the induction of resistance against TIA. Hence, we suggest that the silencing of EZH2 using RNA interference can be an effective and safe approach to help defeat the MOLT-4 cell resistance against TIA.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , ARN Interferente Pequeño/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Estructura Molecular , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
MicroRNAs are characterized as small, single-stranded, non-coding RNA molecules that bind to their target mRNA to prevent protein synthesis. MicroRNAs regulate various normal processes; however, they are aberrantly regulated in many cancers. They control the expression of various genes, including cancer-related genes. This causes microRNAs to be considered as a good target for further investigations for designing novel therapeutic strategies. Since miR124 is known for some time already, it has a tumor-suppressing role in various cancers. Numerous studies indicate its definite roles in malignant processes such as epithelial-to-mesenchymal transition, cell cycle arrest, metastasis, cancer stem cell formation and induction of apoptosis. However, some studies have indicated a dual role for miR-124 in oncogenic processes like autophagy and multi-drug resistance. In this article, we will review recent researches on the biological functions and clinical implications of miR-124. Subsequently, we will discuss future perspectives in terms of the roles of this miRNA in cancers.
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MicroARNs/genética , Neoplasias/genética , Neoplasias/patología , Animales , HumanosRESUMEN
MicroRNAs (miRNAs) that are characterized by small, noncoding RNA have an essential role in the pathogenesis of human diseases, including cancer. Furthermore, miRNAs, as a new paradigm of epigenetic regulators, play an important role in normal development and cellular function. This literature review summarizes the recurrent mechanism of gene regulation through miRNAs and, consequently, the impact of regulated genes on different cellular processes, including proliferation, metastasis, prognosis, and apoptosis. Additionally, what is important to note is that the expression of miRNAs in various cancer cells is different, and miRNAs have various target genes in various cancers. Accordingly, a proper understanding of gene regulation by miRNAs contributes to new perspectives in miRNA-based therapeutic strategies. SIGNIFICANCE OF THE STUDY: MiRNAs are considered as a crucial regulator of gene expression. The genes also play an important role in the expression of miRNAs; as a result, there is a relationship between them. In recent years, targeted therapy with miRNAs has been a significant challenge. Studying the mechanisms through which miRNAs regulate various cancer cell processes, including apoptosis, proliferation, and metastasis, is very critical in the treatment of cancer through miRNAs. Definitely, a proper understanding of the impacts of aberrant expression of miRNAs on cancer cell processes leads to new therapeutic strategies in the targeted therapy with miRNAs.