RESUMO
BACKGROUND/PURPOSE: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study. METHODS: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). RESULTS: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89). CONCLUSION: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials. TRIAL REGISTRATION: NCT02042144.
Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Piridinas , TaiwanRESUMO
Glucagon is important for regulating lipid metabolism in part through its inhibition of fatty acid synthesis in adipocytes. Acetyl-CoA carboxylase 1 (ACC1) is the rate-limiting enzyme for fatty acid synthesis. Glucagon has been proposed to activate cAMP-dependent protein kinase A (PKA), which phosphorylates ACC1 to attenuate the lipogenic activity of ACC1. Because AMP-activated protein kinase (AMPK) also inhibits fatty acid synthesis by phosphorylation of ACC1, we examined the involvement of AMPK and its upstream kinase in the glucagon-elicited signaling in adipocytes in vitro and in vivo. LC-MS-MS analysis suggested that ACC1 was phosphorylated only at Ser(79), an AMPK-specific site, in glucagon-treated adipocytes. Pharmacological inhibitors and siRNA knockdown of AMPK or PKA in adipocytes demonstrate that glucagon regulates ACC1 and ACC2 activity through AMPK but not PKA. By using Ca(2+)/calmodulin-dependent protein kinase kinase-ß knockout (CaMKKß(-/-)) mice and cultured adipocytes, we further show that glucagon activates the CaMKKß/AMPK/ACC cascade. Additionally, fasting increases the phosphorylation of AMPK and ACC in CaMKKß(+/+) but not CaMKKß(-/-) mice. These results indicate that CaMKKß/AMPK signaling is an important molecular component in regulating lipid metabolism in adipocytes responding to glucagon and could be a therapeutic target for the dysregulation of energy storage.
Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/enzimologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glucagon/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células 3T3 , Proteínas Quinases Ativadas por AMP , Tecido Adiposo Branco/fisiologia , Animais , Western Blotting , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Proteínas Quinases Dependentes de AMP Cíclico/genética , Indicadores e Reagentes , Lipogênese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Estimulação Química , Espectrometria de Massas em Tandem , TransfecçãoRESUMO
In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B(1) (AFB(1)) and reduces both AFB(1)-DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt-/-) mice developed HCC, with first dysplastic hepatocellular nodules detected at mean ages of 17 and 16.5 months, respectively. In our study, we tested our hypothesis that male and female Gnmt-/- mice are susceptible to AFB(1) carcinogenesis, and that the absence of Gnmt expression may accelerate AFB(1)-induced liver tumorigenesis. We inoculated Gnmt-/- and wild-type mice intraperitoneally with AFB(1) at 7 days and 9 weeks of age and periodically examined them using ultrasound. Dysplastic hepatocellular nodules were detected in six of eight males and five of five females at 12.7 and 12 months of ages, respectively. Dysplastic hepatocellular nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt-/- mice were diagnosed as having HCC, â¼6 months earlier than AFB(1)-treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were downregulated in AFB(1)-treated Gnmt-/- mice: Cyp1a2, Cyp3a44, Cyp2d22, Gsta4 and Abca8a. In summary, we observed overall higher susceptibility to AFB(1)-related HCC in Gnmt-/- mice, further evidence that GNMT overexpression is an important contributing factor to liver cancer resistance.
Assuntos
Aflatoxina B1/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Glicina N-Metiltransferase/deficiência , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Autopsia , Carcinoma Hepatocelular/enzimologia , Cruzamentos Genéticos , Citocromo P-450 CYP1A2/deficiência , Citocromo P-450 CYP1A2/genética , Sistema Enzimático do Citocromo P-450/deficiência , Sistema Enzimático do Citocromo P-450/genética , Família 2 do Citocromo P450 , Primers do DNA , Feminino , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Glutationa Transferase/deficiência , Glutationa Transferase/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos , Transcrição GênicaRESUMO
OBJECTIVE: Cellular defenses against allergens and reactive oxygen species (ROS) exposure are critical in the pathogenesis of asthma. CD14 is a receptor for various bacterial products, such as lipopolysaccharides (LPS), and is also a mediator of inflammatory processes. Manganese superoxide dismutase (MnSOD) is an ROS scavenger, and myeloperoxidase (MPO) can convert hydrogen peroxide into hypochlorous acid; thus, they are considered to be involved in inflammatory defense. The authors conducted a case-control study to evaluate the susceptibility to childhood asthma based on CD14, MnSOD, and MPO genes. METHODS: The CD14 -260, MnSOD -9, and MPO -463 genotypes were identified by polymerase chain reactions for 116 asthmatic children and 232 healthy controls. Questionnaires were administered to obtain demographic characteristics. Allergen testing used common Taiwanese aeroallergens. RESULTS: A higher level of parental education, family history of asthma, incense burning at home, allergen-test positive, and the MnSOD Val-Ala/Ala-Ala genotypes (matched relative risk = 2.0; 95% confidence interval = 1.0-4.2) were significantly associated with childhood asthma. Interactions between CD14, MnSOD, MPO genotypes and allergy status were significantly associated with asthma risk in these children (all p <.001). Furthermore, atopic cases with MnSOD Val-Ala/Ala-Ala (log eosinophil 2.66/mm(3), log total serum immunoglobulin E [IgE] 2.48 IU/ml) or Val-Val (log eosinophil 2.61/mm(3), log total serum IgE 2.63 IU/ml) genotypes had elevated eosinophil counts and total serum IgE levels as compared to nonatopic cases with MnSOD Val-Val genotype (log eosinophil 2.27/mm(3), log total serum IgE 1.83 IU/ml). CONCLUSIONS: Susceptible MnSOD genotypes might modulate the development of asthma in Taiwanese children.
Assuntos
Asma/epidemiologia , Asma/genética , Hiper-Reatividade Brônquica/genética , Predisposição Genética para Doença/epidemiologia , Superóxido Dismutase/genética , Fatores Etários , Asma/diagnóstico , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Seguimentos , Genótipo , Humanos , Incidência , Masculino , Polimorfismo Genético , Probabilidade , Espécies Reativas de Oxigênio/metabolismo , Valores de Referência , Medição de Risco , Fatores Sexuais , Inquéritos e Questionários , Taiwan/epidemiologiaRESUMO
UNLABELLED: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. To establish a Gnmt knockout mouse model, 2 lambda phage clones containing a mouse Gnmt genome were isolated. At 11 weeks of age, the Gnmt-/- mice had hepatomegaly, hypermethioninemia, and significantly higher levels of both serum alanine aminotransferase and hepatic S-adenosylmethionine. Such phenotypes mimic patients with congenital GNMT deficiencies. A real-time polymerase chain reaction analysis of 10 genes in the one-carbon metabolism pathway revealed that 5,10-methylenetetrahydrofolate reductase, S-adenosylhomocysteine hydrolase (Ahcy), and formiminotransferase cyclodeaminase (Ftcd) were significantly down-regulated in Gnmt-/- mice. This report demonstrates that GNMT regulates the expression of both Ftcd and Ahcy genes. Results from pathological examinations indicated that 57.1% (8 of 14) of the Gnmt-/- mice had glycogen storage disease (GSD) in their livers. Focal necrosis was observed in male Gnmt-/- livers, whereas degenerative changes were found in the intermediate zones of female Gnmt-/- livers. In addition, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes were observed in the Gnmt-/- mice. A real-time polymerase chain reaction analysis of genes involved in the gluconeogenesis pathways revealed that the following genes were significantly down-regulated in Gnmt-/- mice: fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphate transporter. CONCLUSION: Because Gnmt-/- mice phenotypes mimic those of patients with GNMT deficiencies and share several characteristics with GSD Ib patients, we suggest that they are useful for studies of the pathogenesis of congenital GNMT deficiencies and the role of GNMT in GSD and liver tumorigenesis.
Assuntos
Glicina N-Metiltransferase/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Glicogênio/metabolismo , Hepatite Crônica/metabolismo , Fígado/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Alanina Transaminase/sangue , Animais , Mapeamento Cromossômico , Modelos Animais de Doenças , Regulação para Baixo , Embrião de Mamíferos/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Homocisteína/sangue , Fígado/patologia , Metionina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , Proteínas/metabolismo , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismoRESUMO
Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/fisiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-ß1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/enzimologia , Invasividade Neoplásica/patologia , Proteínas Celulares de Ligação ao Retinol/metabolismo , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Células Cultivadas , Imunoprecipitação da Cromatina , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite a general repression of translation under hypoxia, cells selectively upregulate a set of hypoxia-inducible genes. Results from deep sequencing revealed that Let-7 and miR-103/107 are hypoxia-responsive microRNAs (HRMs) that are strongly induced in vascular endothelial cells. In silico bioinformatics and in vitro validation showed that these HRMs are induced by HIF1α and target argonaute 1 (AGO1), which anchors the microRNA-induced silencing complex (miRISC). HRM targeting of AGO1 resulted in the translational desuppression of VEGF mRNA. Inhibition of HRM or overexpression of AGO1 without the 3' untranslated region decreased hypoxia-induced angiogenesis. Conversely, AGO1 knockdown increased angiogenesis under normoxia in vivo. In addition, data from tumor xenografts and human cancer specimens indicate that AGO1-mediated translational desuppression of VEGF may be associated with tumor angiogenesis and poor prognosis. These findings provide evidence for an angiogenic pathway involving HRMs that target AGO1 and suggest that this pathway may be a suitable target for anti- or proangiogenesis strategies.
Assuntos
Proteínas Argonautas/genética , Fatores de Iniciação em Eucariotos/genética , MicroRNAs/genética , Neovascularização Patológica/metabolismo , Regiões 3' não Traduzidas , Animais , Proteínas Argonautas/metabolismo , Proteínas Argonautas/fisiologia , Sequência de Bases , Sítios de Ligação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Hipóxia Celular , Linhagem Celular Tumoral , Fatores de Iniciação em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/fisiologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , MicroRNAs/metabolismo , Transplante de Neoplasias , Especificidade de Órgãos , Interferência de RNA , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-alpha-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumorigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadherin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function.