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1.
Toxicol Appl Pharmacol ; 330: 84-92, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28716507

RESUMO

DNA topoisomerase 2, which is ubiquitously expressed in eukaryotic cells, is an essential nuclear enzyme that promotes cell survival by regulating DNA topology and chromatid separation. This enzyme has been validated as a target for anticancer agent screening. It can be poisoned by common chemotherapeutics, such as etoposide and doxorubicin, which leads to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. However, recent studies have suggested that the topoisomerase 2a isozyme is predominantly responsible for the carcinogenic side effects associated with etoposide and doxorubicin chemotherapy. Thus, we need to find a promising topoisomerase 2-targeting anticancer agent that avoids these carcinogenic side effects. Recent studies have found that cryptotanshinone has obvious anticancer activities against diverse cancer cells. Here, we demonstrate that cryptotanshinone markedly decreases the steady-state mRNA level of topoisomerase 2a, thereby decreasing the protein and activity levels of this enzyme. Moreover, cryptotanshinone exhibited dramatic in vitro and in vivo antitumor activity with low toxicity to normal tissues. Collectively, our findings support the development of cryptotanshinone as a promising candidate for treating cancer by targeting topoisomerase 2a.


Assuntos
Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenantrenos/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/biossíntese , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Leuk Res ; 47: 116-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27318093

RESUMO

Aberrant hypermethylation of tumor suppressor genes is known to play an important role in the development of many tumors, and aberrant DNA hypermethylation was recently identified in hematologic malignancies, where it is thought to hold relevance in leukemogenesis. Here, we report that there are differences in the DNA methylation patterns seen in normal peripheral blood and two T-cell leukemia cell lines. We identify nine genes (CLEC4E, CR1, DBC1, EPO, HAL-DOA, IGF2, IL12B, ITGA1, and LMX1B) that are significantly hypermethylated in T-cell leukemias cell lines, and suggest that aberrant hypermethylation of these normally unmethylated genes may induce their transcriptional and expressional silencing. Furthermore, we observed that the expression levels of DNMT1 and DNMT3a were significantly decreased by 5-aza-2'-deoxycytidine (5-Aza-dC), which is a demethylation agent known to deplete DNA methyltransferases (DNMTs) in leukemia cancer cells and restore the expression levels of their target genes in Jurkat cells. This result suggests that the overexpression of DNMTs could contribute to the development of T-cell leukemias by inducing hypermethylation of the target genes. Together, our results show that aberrant hypermethylation is an important molecular mechanism in the progression of T-cell leukemias, and thus could prove useful as a prognostic and/or diagnostic marker. Moreover, 5-Aza-dC might be a promising candidate for the treatment of T-cell leukemia.


Assuntos
Metilação de DNA , Inativação Gênica , Leucemia de Células T/genética , Adulto , Células Sanguíneas , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia de Células T/diagnóstico , Leucemia de Células T/terapia , Masculino
3.
Cancer Biol Ther ; 16(4): 558-66, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25719218

RESUMO

Accumulating evidence suggests that changes in methylation patterns may help mediate the sensitivity or resistance of cancer cells to ionizing radiation. The present study provides evidence for the involvement of radioresistance-induced DNA methylation changes in tumor radioresistance. We established radioresistant laryngeal cancer cells via long-term fractionated irradiation, and examined differences in DNA methylation between control and radioresistant laryngeal cancer cells. Interestingly, we found that the promoter-CpG islands of 5 previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2, GFI1, and IL12B) were significantly altered in the radioresistant laryngeal cancer cells. Furthermore, the demethylation of these gene promoters with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the radioresistant laryngeal cancer cells to irradiation, indicating that changes in DNA methylation contributed to their radioresistance. Of the tested genes, the expression and activity levels of TOPO2A were tightly associated with the radioresistant phenotype in our system, suggesting that the hypermethylation of TOPO2A might be involved in this radioresistance. Collectively, our data suggest that radiation-induced epigenetic changes can modulate the radioresistance of laryngeal cancer cells, and thus may prove useful as prognostic indicators for radiotherapy.


Assuntos
Antígenos de Neoplasias/genética , Carcinoma de Células Escamosas/genética , Metilação de DNA/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Laríngeas/genética , Tolerância a Radiação/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Ilhas de CpG/efeitos dos fármacos , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Decitabina , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Tolerância a Radiação/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética
4.
Cancer Biol Ther ; 14(11): 1007-15, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24005240

RESUMO

Camptothecins are commonly used chemotherapeutics; in some models, they enhance signaling via the mitogen-activated protein kinase (MAPK) pathway through effects on upstream kinases. To evaluate the impact of camptothecin (CPT) on MAPKs in human colon cancer, we studied HCT116 and CaCo2 colon cancer cells. We found that HCT116 cells highly express mitogen-activated protein kinase phosphatase-1 (MKP1), which selectively inactivates extracellular signal-regulated kinase (ERK), whereas MKP1 levels were undetectable in CaCo2 cells. CPT did not affect ERK activity in CaCo2 cells, but did induce a striking increase in ERK activity in HCT116 cells in association with a corresponding decrease in MKP1. The reduction in MKP1 expression occurred at a posttranscriptional level and was blocked by the proteasome inhibitor MG132, whereas that CPT-induced downregulation of MKP1 was not due to proteasome-mediated degradation. Treatment of HCT116 cells with CPT induced a sustained activation of nuclear ERK, which was required for CPT-induced apoptosis. P38 and JNK activity were unaffected by CPT, suggesting that the effects of CPT are mediated specifically by ERK. These results suggest that targeting dual-specificity MAPK phosphatases in colon cancer cells may be a viable strategy for optimizing camptothecin-based therapeutic protocols.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Neoplasias do Colo/metabolismo , Fosfatase 1 de Especificidade Dupla/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Adenocarcinoma/patologia , Células CACO-2 , Neoplasias do Colo/patologia , Ativação Enzimática , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo
5.
Yonsei Med J ; 52(2): 242-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21319341

RESUMO

PURPOSE: Low grade inflammation is a well-known characteristic in obese subjects. We investigated body weight changes and inflammatory markers after 12-week intervention trial. MATERIALS AND METHODS: Twenty-six obese subjects were enrolled and 19 (13 men and 6 women) completed the study. Sibutramine is an FDA-approved drug for body weight control; therefore, we chose this drug as the standard treatment medication in this study. Patients were randomly allocated to receive an anti-inflammatory agent (Diacerein treatment group; n = 12) or placebo (n = 7) for 12 weeks. Anthropometry, body proportion by dual-energy X-ray absorptiometry, and metabolic parameters at the beginning and end of study were measured and compared. RESULTS: The treatment group had a tendency towards more reduction in anthropometry as compared to the placebo group, in body weight reduction (-7.0 kg vs. -4.6 kg), body mass index (-2.51 kg/m² vs. -1.59 kg/m²), and waist circumference (-7.3 cm vs. -4.4 cm). These reductions were not statistically significant. Changes in levels of high-sensitivity C-reactive protein and adiponectin in the treatment group were more favorable than in the placebo group. CONCLUSION: This small pilot study showed no statistical difference for changes in anthropometry, and inflammatory markers between the two groups. Therefore, we could not find any additional effects of Diacerein on weight loss and inflammatory variables in this study.


Assuntos
Antraquinonas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Ciclobutanos/uso terapêutico , Obesidade/tratamento farmacológico , Redução de Peso/imunologia , Absorciometria de Fóton , Adiponectina/sangue , Adulto , Depressores do Apetite/uso terapêutico , Proteína C-Reativa/análise , Método Duplo-Cego , Feminino , Humanos , Inflamação , Lipoproteínas LDL/sangue , Masculino , Obesidade/imunologia , Projetos Piloto , Fator de Necrose Tumoral alfa/sangue , Circunferência da Cintura/efeitos dos fármacos , Circunferência da Cintura/imunologia , Redução de Peso/efeitos dos fármacos
6.
J Korean Med Sci ; 25(12): 1771-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21165293

RESUMO

Obese individuals are less able to oxidize fat than non-obese individuals. Caloric reduction or fasting can detect ketonuria. We investigated the differences of metabolic parameters in the presence of ketonuria after a minimum 8 hr fast in a cross-sectional analysis of 16,523 Koreans (6,512 women and 10,011 men). The relationship between the presence of ketonuria of all subjects and prevalence of obesity, central obesity, metabolic syndrome, and obesity-related metabolic parameters were assessed. The ketonuria group had lower prevalence of obesity, central obesity, and metabolic syndrome than the non-ketonuria group. In addition, all metabolic parameters (including body weight, waist circumference, blood glucose, high-density lipoprotein, triglyceride, blood pressure, and insulin) were favorable in the ketonuria group than in the non-ketonuria group, even after adjustment for age, tobacco use, and alcohol consumption. The odds ratios of having obesity (odds ratio [OR]=1.427 in women, OR=1.582 in men, P<0.05), central obesity (OR=1.675 in women, OR=1.889 in men, P<0.05), and metabolic syndrome (OR=3.505 in women, OR=1.356 in men, P<0.05) were increased in the non-ketonuria group compared to the ketonuria group. The presence of ketonuria after at least an 8 hr fast may be indicative of metabolic superiority.


Assuntos
Jejum , Cetose/complicações , Síndrome Metabólica/complicações , Glicemia/análise , Pressão Sanguínea , Peso Corporal , Estudos Transversais , Feminino , Humanos , Insulina/sangue , Cetose/diagnóstico , Lipoproteínas HDL/sangue , Masculino , Síndrome Metabólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Razão de Chances , Fatores de Tempo , Triglicerídeos/sangue , Circunferência da Cintura
7.
Biol Trace Elem Res ; 129(1-3): 28-35, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19043675

RESUMO

Little is known about hair minerals in cancer patients, and serum iron level has been shown to be elevated in breast cancer patients. Therefore, the aim of this study was to evaluate hair iron and hair minerals' level related to hair iron in breast cancer patients compared to controls. We compared hair mineral analysis data of 40 breast cancer subjects with age and body mass index-matched normal control data (n = 144) by cross-sectional analysis. All breast cancer patients were newly diagnosed at one Breast Cancer Center in Ajou University and had their hair cut before anti-cancer chemotherapy, and the normal controls (without breast cancer) also had their hair cut for various reasons in out-patient clinics of the Department of Family Practice and Community Health. Breast cancer patients had low calcium, magnesium, iron, copper, manganese, and zinc, whereas they had high arsenic, sodium, and potassium compared with the normal control. The hair iron level was positively correlated with hair calcium (r = 0.761, P < 0.001), magnesium (r = 0.643, P < 0.001), and manganese (r = 0.550, P < 0.001) and negatively correlated with arsenic (r = -0.537, P < 0.001). The hair iron level was significantly associated with the hair calcium (beta = 0.778, P < 0.001) and manganese (beta = 0.240, P < 0.001) by using multiple linear regression analysis. We observed different hair mineral patterns in breast cancer patients compared to normal controls. Especially, hair iron level was significantly reduced and associated with hair calcium and manganese levels.


Assuntos
Neoplasias da Mama/diagnóstico , Cabelo/química , Ferro/análise , Oligoelementos/análise , Fatores Etários , Índice de Massa Corporal , Peso Corporal , Neoplasias da Mama/metabolismo , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade
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