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1.
Mol Oncol ; 13(7): 1589-1604, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162799

RESUMO

Activation of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway induces glial differentiation of glioblastoma (GBM) cells, but the mechanism by which microRNA (miRNA) regulate this process remains poorly understood. In this study, by performing miRNA genomics and loss- and gain-of-function assays in dibutyryl-cAMP-treated GBM cells, we identified a critical negative regulator, hsa-miR-1275, that modulates a set of genes involved in cancer progression, stem cell maintenance, and cell maturation and differentiation. Additionally, we confirmed that miR-1275 directly and negatively regulates the protein expression of glial fibrillary acidic protein (GFAP), a marker of mature astrocytes. Of note, tri-methyl-histone H3 (Lys27) (H3K27me3), downstream of the PKA/polycomb repressive complex 2 (PRC2) pathway, accounts for the downregulation of miR-1275. Furthermore, decreased miR-1275 expression and induction of GFAP expression were also observed in dibutyryl-cAMP-treated primary cultured GBM cells. In a patient-derived glioma stem cell tumor model, a cAMP elevator and an inhibitor of H3K27me3 methyltransferase inhibited tumor growth, induced differentiation, and reduced expression of miR-1275. In summary, our study shows that epigenetic inhibition of miR-1275 by the cAMP/PKA/PRC2/H3K27me3 pathway mediates glial induction of GBM cells, providing a new mechanism and novel targets for differentiation-inducing therapy.

2.
J Immunol Res ; 2019: 4730507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093510

RESUMO

Background: Kawasaki disease (KD) is a systemic form of self-limited vasculitis in children less than five years old, and the main complication is coronary artery injury. However, the etiology of KD remains unclear. The IL-1B polymorphisms rs16944 GG and rs1143627 AA and their diplotype GA/GA have been associated with significantly increased risk of intravenous immunoglobulin (IVIG) resistance in a Taiwanese population, but the relationship between rs16944 A/G and rs1143627 G/A and coronary artery lesions (CALs) in patients with KD has not been investigated. The present study is aimed at investigating whether the rs16944 A/G and rs1143627 G/A polymorphisms in IL-1B were associated with KD susceptibility and CALs in a southern Chinese population. Methods and Results: We recruited 719 patients with KD and 1401 healthy children. Multiplex PCR was used to assess the genotypes of single nucleotide polymorphisms (SNPs), including two SNPs of IL-1B, rs16944 A/G and rs1143627 G/A. According to the results, no significant association was observed between the IL-1B (rs16944 and rs1143627) polymorphisms and KD risk in the patients compared with the healthy controls in our southern Chinese population. However, in further stratified analysis, we found that children younger than 12 months with the rs16944 GG and rs1143627 AA genotypes of IL-1B had a higher risk of CALs than those with the AA/AG genotypes of rs16944 and GG/AG genotypes of rs1143627 (OR = 2.28, 95% CI = 1.32-3.95, P = 0.0032, adjusted OR = 2.33, 95% CI = 1.34-4.04, P = 0.0027). Conclusions: Our results indicated that there was no association between the rs16944 A/G and rs1143627 G/A gene polymorphisms and KD susceptibility. However, the rs16944 GG and rs1143627 AA genotypes of IL-1B may significantly impact the risk of CAL formation in children younger than 12 months, which may contribute to the pathogenesis of KD. These findings need further validation in multicenter studies with larger sample sizes.


Assuntos
Vasos Coronários/patologia , Predisposição Genética para Doença/etnologia , Interleucina-1beta/genética , Síndrome de Linfonodos Mucocutâneos/genética , Adolescente , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/etnologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
3.
Biosci Rep ; 39(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31043452

RESUMO

Kawasaki disease (KD) is also called mucocutaneous lymph node syndrome and is an acute febrile pediatric disease characterized by systemic vasculitis. KD typically occurs in children 5 years old or younger and occurs more often in males than in females. miRNA-608 has been reported to interact with interleukin-6 and affect innate immunity. The immune-mediated inflammation could induce the occurrence of KD; however, there is no previous research focused on the relationship between miRNA-608 polymorphism and the KD risk. The present study explored the correlation between the miRNA-608 rs4919510 G>C polymorphism and the risk for KD. We recruited 532 patients with KD and 623 controls to genotype the miRNA-608 rs4919510 G>C polymorphism with a TaqMan allelic discrimination assay. Single-locus analysis showed no significant association between miRNA rs4919510 G>C polymorphism and KD susceptibility. However in an analysis stratified by age, gender, and coronary artery lesion (CAL), we found a relationship between the miRNA-608 rs4919510 G>C polymorphism and KD susceptibility. When KD patients were stratified by coronary injury, the CG/CC genotypes of the miRNA-608 rs4919510 G>C polymorphism contributed to a higher occurrence of KD than that was found in the GG genotype patients (adjusted odds ratio = 0.74, 95% CI = 0.56-0.98, P = 0.033). The present study demonstrated that the miRNA-608 rs4919510 G>C polymorphism may have a CAL-related relationship with KD susceptibility that has not been previously revealed.

4.
J Cell Physiol ; 234(11): 20577-20583, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30982978

RESUMO

Genetics might play various roles in susceptibility to recurrent miscarriage, and previous studies suggest that some gene polymorphisms might be associated with abortion and breast cancer onset. Colon cancer-associated transcript 2 (CCAT2) is a novel long noncoding RNA (lncRNA) transcript that might be correlated with susceptibility to multiple cancers, including breast cancer. However, whether lncRNA CCAT2 polymorphisms are related to susceptibility to recurrent miscarriage is unclear. We genotyped two lncRNA CCAT2 polymorphisms (rs6983267 and rs3843549) in 248 patients with recurrent miscarriage and 392 controls through a TaqMan real-time polymerase chain reaction assay, and the strength of each association was evaluated via 95% confidence intervals (CIs) and odds ratios (ORs). Our results showed that the rs6983267 G allele in lncRNA CCAT2 was associated with decreased susceptibility to recurrent miscarriage (TG vs. TT: adjusted OR = 0.603; 95% CI = 0.420-0.866; p = 0.0062; GG/TG vs. TT: adjusted OR = 0.620; 95% CI = 0.441-0.873; p = 0.0061). The combined analysis of the two protective polymorphisms (rs3843549 AA and rs6983267 TG/GG) revealed that individuals with two unfavorable alleles exhibited a lower risk of recurrent miscarriage than those with no or only one unfavorable allele (adjusted OR = 0.531; 95% CI = 0.382-0.739). Moreover, the decreased risk associated with the two protective alleles was most obvious in women aged less than 35 years (OR = 0.551; 95% CI = 0.378-0.8803; p = 0.0019) and in women with two to three miscarriages (adjusted OR = 0.466; 95% CI = 0.318-0.683; p < 0.0001). In conclusion, our study indicates that the rs6983267G allele might contribute to a decreased risk of recurrent miscarriage in the South Chinese population.

5.
J Gene Med ; 21(1): e3066, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576025

RESUMO

BACKGROUND: Activated-platelet increases the risk of thrombosis in Kawasaki disease (KD) patients with a coronary artery aneurysm (CAA). The ADP pathway is one of the platelet activation and aggregation pathways. The P2RY12 gene encodes the ADP receptor that is highly concentrated on platelets. However, few studies have reported on P2RY12 in relation to KD susceptibility with or without CAA. METHODS: We recruited 1335 healthy controls and 776 KD patients, including 103 with CAA, and selected five P2RY12 polymorphisms: rs9859538, rs1491974, rs7637803, rs6809699 and rs2046934. The present study focused on the relationship between the P2RY12 polymorphisms and KD with or without CAA. RESULTS: Among all of the selected polymorphisms, single-locus analysis showed no significant association between the P2RY12 polymorphism and KD susceptibility. However, we found a significant relationship between rs7637803 and CAA risk in KD patients [CT versus CC: odds ratio (OR) = 0.41, 95% confidence interval (CI) = 0.22-0.75; p = 0.0041; TT versus CC: OR = 2.90, 95% CI = 1.12-7.46; p = 0.0276]. Stratification analysis by age in KD patients indicated that the rs7637803 TT genotype increased CAA formation risk among children aged (OR = 3.90, 95% CI = 1.42-10.69; p = 0.0081) and increased the onset risk of CAA in males (OR = 6.28, 95% CI = 2.01-19.65; p = 0.0016). The combined effect of the five selected P2RY12 risk genotypes with the KD patients compared to non-mutated P2RY12 genotypes (score: 0) showed that patients with P2RY12 genotype polymorphisms (score: 1-5) had a significantly increased CAA risk (p = 0.0086). Stratification analysis for the severity of CAA found that the rs7637803 TT genotype reduced giant CAA (GCAA) risk (OR = 4.60, 95% CI = 1.70-12.41; p = 0.0026). CONCLUSIONS: The results of the present study indicate that the P2RY12 rs7637803 genotype might be used as a biomarker to predict the occurrence of GCAA.

6.
Front Psychol ; 9: 1671, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327621

RESUMO

Studies on Chinese dictation difficulties have focused on visual processing and phonological processing. In recent decades, attention has shifted to the ability to bind visual and auditory information. However, such studies are scarce and rarely focus on how this ability influences children's learning and writing of Chinese characters. In this study, a group of children with Chinese dictation difficulties and a control group without such difficulties were instructed to learn rarely used Chinese characters under three learning modes: grapheme learning, syllable learning, and grapheme-syllable learning. Participants' learning time and writing accuracy were recorded under each learning mode. Findings showed that under the grapheme learning mode, learning time and writing accuracy failed to differ significantly between the two groups. However, under the grapheme-syllable learning mode, the writing accuracy of children with dictation difficulties was significantly lower than controls. These findings, taken together, suggested that for children with dictation difficulties, learning graphemes and syllables at the same time did not improve their writing performance as much as the controls. Under the syllable learning mode, learning time and writing accuracy failed to differ significantly between the two groups. The findings contributed to a better understanding of the Chinese dictation difficulties.

7.
Nat Commun ; 9(1): 4342, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337542

RESUMO

Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers.

9.
Nat Commun ; 9(1): 1524, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29670091

RESUMO

Oncolytic virus is an attractive anticancer agent that selectively lyses cancer through targeting cancer cells rather than normal cells. Although M1 virus is effective against several cancer types, certain cancer cells present low sensitivity to it. Here we identified that most of the components in the cholesterol biosynthesis pathway are downregulated after M1 virus infection. Further functional studies illustrate that mevalonate/protein farnesylation/ras homolog family member Q (RHOQ) axis inhibits M1 virus replication. Further transcriptome analysis shows that RHOQ knockdown obviously suppresses Rab GTPase and ATP-mediated membrane transporter system, which may mediate the antiviral effect of RHOQ. Based on this, inhibition of the above pathway significantly enhances the anticancer potency of M1 virus in vitro, in vivo, and ex vivo. Our research provides an intriguing strategy for the rational combination of M1 virus with farnesyl transferase inhibitors to enhance therapeutic efficacy.

10.
J Virol ; 92(6)2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29263275

RESUMO

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.


Assuntos
Autofagia/imunologia , Endorribonucleases/deficiência , Glioma/terapia , Proteínas de Neoplasias/deficiência , Terapia Viral Oncolítica , Vírus Oncolíticos , Proteínas Serina-Treonina Quinases/deficiência , Togaviridae , Animais , Autofagia/genética , Linhagem Celular Tumoral , Cercopithecus aethiops , Cricetinae , Endorribonucleases/imunologia , Feminino , Glioma/genética , Glioma/imunologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/imunologia , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Hum Gene Ther ; 29(8): 950-961, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28750564

RESUMO

Oncolytic virotherapy is a novel and intriguing treatment strategy for cancer therapy. However, the clinical potential of oncolytic virus as single agent is limited. M1 virus is a promising oncolytic virus that has been tested in preclinical studies. In this study, we investigated the effect of the combination use of M1 virus and Bcl-2 family inhibitors. A chemical compounds screening including ten Bcl-2 family inhibitors demonstrated that pan-Bcl-2 inhibitors selectively augmented M1 virus oncolysis in cancer cells at very low doses. The mechanism of the enhanced antitumor effect of pan-Bcl-2 inhibitors with M1 virus is mainly due to the inhibition of Bcl-xL, which synergizes with M1-induced upregulation of Bak to trigger apoptosis. In xenograft mouse models and patient-derived tumor tissues, the combination of M1 and pan-Bcl-2 inhibitors significantly inhibited tumor growth and prolonged survival, suggesting the potential therapeutic value of this strategy. These findings offer insights into the synergy between Bcl-xL inhibition and oncolytic virus M1 as a combination anticancer treatment modality.

12.
Sci Transl Med ; 9(404)2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835517

RESUMO

Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus-suppressed inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential.


Assuntos
Antineoplásicos/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Vírus Oncolíticos/metabolismo , Proteína com Valosina/antagonistas & inibidores , Animais , Apoptose , Efeito Espectador , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Terapia Combinada , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Hepáticas/patologia , Vírus Oncolíticos/patogenicidade , Primatas , Proteínas Serina-Treonina Quinases/metabolismo , Proteína com Valosina/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo
13.
Proc Natl Acad Sci U S A ; 114(26): 6812-6817, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28607091

RESUMO

Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.


Assuntos
Apoptose/efeitos dos fármacos , Efeito Espectador/efeitos dos fármacos , Neoplasias Experimentais/terapia , Oligopeptídeos/farmacologia , Vírus Oncolíticos/fisiologia , Peptidomiméticos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Apoptose/imunologia , Efeito Espectador/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Humanos , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia
14.
Cell Rep ; 18(2): 468-481, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28076790

RESUMO

Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/patologia , Diferenciação Celular , AMP Cíclico/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Glicólise , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/ultraestrutura , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Perfilação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/genética , Glioblastoma/ultraestrutura , Glicólise/efeitos dos fármacos , Humanos , Biogênese de Organelas , Fosforilação Oxidativa/efeitos dos fármacos , Proteômica , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncotarget ; 7(30): 48443-48455, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27374176

RESUMO

Oncolytic virotherapy is an emerging and promising treatment modality that uses replicating viruses as selective antitumor agents. Here, we report that a classical protein kinase A (PKA) inhibitor, H89, synergizes with oncolytic virus M1 in various cancer cells through activation of Epac1 (exchange protein directly activated by cAMP 1). H89 substantially increases viral replication in refractory cancer cells, leading to unresolvable Endoplasmic Reticulum stress, and cell apoptosis. Microarray analysis indicates that H89 blunts antiviral response in refractory cancer cells through retarding the nuclear translocation of NF-κB. Importantly, in vivo studies show significant antitumor effects during M1/H89 combination treatment. Overall, this study reveals a previously unappreciated role for H89 and demonstrates that activation of the Epac1 activity can improve the responsiveness of biotherapeutic agents for cancer.


Assuntos
Alphavirus/fisiologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Isoquinolinas/uso terapêutico , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Sulfonamidas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Terapia Combinada/métodos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/genética , Retículo Endoplasmático/patologia , Retículo Endoplasmático/ultraestrutura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Neoplasias/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Fator de Transcrição RelA/metabolismo , Replicação Viral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Hum Gene Ther ; 27(9): 700-11, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27296553

RESUMO

Cancers figure among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next 2 decades. Development of novel therapeutic agents is urgently needed for clinical cancer therapy. Alphavirus M1 is a Getah-like virus isolated from China with a genome of positive single-strand RNA. We have previously identified that alphavirus M1 is a naturally existing oncolytic virus with significant anticancer activity against different kinds of cancer (e.g., liver cancer, bladder cancer, and colon cancer). To support the incoming clinical trial of intravenous administration of alphavirus M1 to cancer patients, we assessed the safety of M1 in adult nonhuman primates. We previously presented the genome sequencing data of the cynomolgus macaques (Macaca fascicularis), which was demonstrated as an ideal animal species for virus infection study. Therefore, we chose cynomolgus macaques of either sex for the present safety study of oncolytic virus M1. In the first round of administration, five experimental macaques were intravenously injected with six times of oncolytic virus M1 (1 × 10(9) pfu/dose) in 1 week, compared with five vehicle-injected control animals. The last two rounds of injections were further completed in the following months in the same way as the first round. Body weight, temperature, complete blood count, clinical biochemistries, cytokine profiles, lymphocytes subsets, neutralizing antibody, and clinical symptoms were closely monitored at different time points. Magnetic resonance imaging was also performed to assess the possibility of encephalitis or arthritis. As a result, no clinical, biochemical, immunological, or medical imaging or other pathological evidence of toxicity was found during the whole process of the study. Our results in cynomolgus macaques suggested the safety of intravenous administration of oncolytic virus M1 in cancer patients in the future.


Assuntos
Alphavirus/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vetores Genéticos/administração & dosagem , Vírus Oncolíticos/imunologia , Alphavirus/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intravenosas , Macaca fascicularis , Masculino , Vírus Oncolíticos/genética
17.
Mol Ther ; 24(1): 156-65, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26373347

RESUMO

Oncolytic virotherapy is a novel and emerging treatment modality that uses replication-competent viruses to destroy cancer cells. Although diverse cancer cell types are sensitive to oncolytic viruses, one of the major challenges of oncolytic virotherapy is that the sensitivity to oncolysis ranges among different cancer cell types. Furthermore, the underlying mechanism of action is not fully understood. Here, we report that activation of cyclic adenosine monophosphate (cAMP) signaling significantly sensitizes refractory cancer cells to alphavirus M1 in vitro, in vivo, and ex vivo. We find that activation of the cAMP signaling pathway inhibits M1-induced expression of antiviral factors in refractory cancer cells, leading to prolonged and severe endoplasmic reticulum (ER) stress, and cell apoptosis. We also demonstrate that M1-mediated oncolysis, which is enhanced by cAMP signaling, involves the factor, exchange protein directly activated by cAMP 1 (Epac1), but not the classical cAMP-dependent protein kinase A (PKA). Taken together, cAMP/Epac1 signaling pathway activation inhibits antiviral factors and improves responsiveness of refractory cancer cells to M1-mediated virotherapy.


Assuntos
Alphavirus/genética , Colforsina/administração & dosagem , AMP Cíclico/metabolismo , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose , Linhagem Celular Tumoral , Colforsina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/genética , Células HCT116 , Humanos , Camundongos , Neoplasias/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética
18.
Proc Natl Acad Sci U S A ; 111(42): E4504-12, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25288727

RESUMO

Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.


Assuntos
Alphavirus/classificação , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/classificação , Animais , Apoptose , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Transplante de Neoplasias , Neoplasias/metabolismo , Interferência de RNA , Análise Serial de Tecidos , Dedos de Zinco
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