RESUMO
Several studies have compared the molecular responses between e14a2 and e13a2 BCR::ABL1 transcripts in chronic myeloid leukemia (CML) patients treated with front-line imatinib, but there were very limited studies on nilotinib or dasatinib-treated patients. We retrospectively analyzed the molecular responses in 1124 CML patients with the e14a2 or e13a2 transcript receiving front-line imatinib, nilotinib or dasatinib treatment. Patients with the e14a2 transcript had higher optimal response rates than those with the e13a2 transcript at 12 months in the imatinib-treated group, and 6 and 12 months in the nilotinib-treated group. The optimal response rates were not significantly different between the two transcripts in the dasatinib-treated group at landmark molecular responses. With a median follow-up time of 48.4 months, higher cumulative incidences of BCR::ABL1 International Scale ≤1% and major molecular response were observed in patients with the e14a2 rather than the e13a2 transcript receiving front-line imatinib or nilotinib treatment, but not in dasatinib-treated patients. The progression-free survival and overall survival did not differ between the two transcripts in all three treatment groups. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front-line tyrosine kinase inhibitor for individual young patients with future potential treatment-free remission.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucopenia , Trombocitopenia , Antineoplásicos/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucopenia/induzido quimicamente , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Taiwan/epidemiologia , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor.
RESUMO
Cantharidin, a natural toxin from blister beetles, has shown potent anticancer activities on many solid tumor cells. Recently, cantharidin and its analogue, norcantharidin, were also shown to suppress nonsolid tumors such as chronic myeloid leukemia, acute myeloid leukemia (AML), and leukemic stem cells. However, there is no available information to address the effects of cantharidic acid (CAC), a hydrolysis product of cantharidin, on human AML cells. The present study showed that CAC, at a range of concentrations (0-20 µM), concentration-dependently inhibited cell proliferation in the HL-60 AML cell line. Western blot and flow cytometric assays demonstrated that CAC induced several features of apoptosis such as sub G1-phase cell increase, phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Moreover, treatment of HL-60 cells with CAC induced concentration- and time- dependent activation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). Only JNK-, but not p38 MAPK-specific inhibitor can reverse the CAC-induced activation of the caspase-8, -9, and -3. We concluded that CAC can induce apoptosis in human leukemic HL-60 cells via a caspases-dependent pathway, and that the apoptosis-inducing effect of CAC can be regulated by JNK activation signaling.
Assuntos
Cantaridina/farmacologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Fase G1 , Células HL-60 , Humanos , Sistema de Sinalização das MAP Quinases , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML.
Assuntos
Cromonas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Apoptose , Caspases/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HL-60 , HumanosRESUMO
BACKGROUND: Avulsion of the aortic valve commissure as a cause of acute aortic valve regurgitation is mostly due to trauma, infective endocarditis, or ascending aortic dissection. Nontraumatic avulsion of the aortic valve commissure is very rare. We reviewed the literature and analyzed potential risk factors of nontraumatic avulsion. CASE PRESENTATION: An 80-year-old male with hypertension was seen in the emergency department with acute onset dyspnea. Echocardiogram revealed left ventricular hypertrophy with adequate systolic function, prolapse of the noncoronary cusp, and incomplete coaptation of the right coronary and noncoronary cusps with severe aortic valve regurgitation. Surgery revealed an avulsion between the left coronary and noncoronary cusps. Histopathology examination of the aortic valve showed myxoid degeneration, fibrosis, and calcification. Examination of the ascending aorta revealed myxoid degeneration and fragmentation of elastic fibers. Aortic valve replacement was performed, and the patient was alive and well 4 years after surgery. A review of the literature showed that more than three-fourths of the similar cases occurred in males, and about half in patients with hypertension and those 60 years of age or older. CONCLUSIONS: In the case of acute aortic regurgitation without a history of trauma, infection, or valvotomy, when 2 prolapsed aortic cusps are observed by echocardiography in the absence of an intimal tear of the ascending aorta, an avulsion of the aortic commissure should be suspected, especially in males with hypertension who are 60 years of age or older.
Assuntos
Insuficiência da Valva Aórtica/etiologia , Valva Aórtica/diagnóstico por imagem , Próteses Valvulares Cardíacas , Doença Aguda , Idoso de 80 Anos ou mais , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/diagnóstico , Insuficiência da Valva Aórtica/cirurgia , Ecocardiografia , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
A 67-year-old man with a biopsy proving prostate diffuse large B-cell lymphoma was referred for an F-FDG PET/CT scan for postchemotherapy treatment monitoring. The FDG PET/CT scan revealed a significant reduction of prostate lymphoma and a prostatorectal fistula formation. The patient developed Klebsiella pneumoniae sepsis, and a follow-up FDG PET/CT 3 months later revealed multifocal lung, bone, and muscle infection. The FDG PET/CT scans of this patient not only demonstrated the effectiveness of chemotherapy for prostate lymphoma but also the complications of a prostatorectal fistula and multiple infectious foci.
Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Fístula Retal/diagnóstico por imagem , Sepse/complicações , Idoso , Fluordesoxiglucose F18 , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/complicações , Compostos Radiofarmacêuticos , Fístula Retal/etiologia , Tomografia Computadorizada por Raios XRESUMO
Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL-60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time-dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII-induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/biossíntese , Leucemia Promielocítica Aguda/tratamento farmacológico , Saponinas/administração & dosagem , Esteroides/administração & dosagem , Caspases/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/biossínteseRESUMO
BACKGROUND: Pterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated. METHODOLOGY AND PRINCIPAL FINDINGS: Results showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B. CONCLUSION: Taken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estilbenos/farmacologia , Caspases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HL-60 , Humanos , Membranas Intracelulares/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lisossomos/metabolismo , Metaloproteinases da Matriz/metabolismoRESUMO
Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Flavonas/farmacologia , Leucemia Mieloide Aguda/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genéticaRESUMO
BACKGROUND: Glabridin, a prenylated isoflavonoid of G. glabra L. roots, has been associated with a wide range of biological properties such as regulation of energy metabolism, estrogenic, neuroprotective, anti-osteoporotic, and skin-whitening in previous studies. However, the effect of glabridin on tumor cells metastasis has not been clearly clarified. Here, the molecular mechanism by which glabridin anticancer effects in human promyelocytic leukemia cells was investigated. METHODOLOGY AND PRINCIPAL FINDINGS: The results showed that glabridin significantly inhibited cell proliferation of four AML cell lines (HL-60, MV4-11, U937, and THP-1). Furthermore, glabridin induced apoptosis of HL-60 cells through caspases-3, -8, and -9 activations and PARP cleavage in dose- and time-dependent manner. Moreover, western blot analysis also showed that glabridin increase phosphorylation of ERK1/2, p38 MAPK and JNK1/2 in dose- and time-dependent manner. Inhibition of p38 MAPK and JNK1/2 by specific inhibitors significantly abolished the glabridin-induced activation of the caspase-3, -8 and -9. CONCLUSION: Taken together, our results suggest that glabridin induced HL-60 cell apoptosis through p38 MAPK and JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Isoflavonas/farmacologia , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HL-60 , Humanos , Isoflavonas/química , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Fenóis/química , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Intercellular adhesion molecule (ICAM)-1, a cell adhesion molecule, is reportedly overexpressed in several cancers and may contribute to tumorgenesis and metastasis. The current study explored the effect of ICAM-1 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. A total of 558 participants, including 279 healthy people and 279 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms of the ICAM-1 gene were assessed by a real-time polymerase chain reaction with the TaqMan assay. After adjusting for other covariants, the individuals carrying at least one G allele at ICAM-1 rs5498 had a 1.603-fold risk of developing UCC than did wild-type (AA) carriers. Furthermore, UCC patients who carried at least one G allele at rs5498 had a higher invasive stage risk (p < 0.05) than did patients carrying the wild-type allele. In conclusion, the rs5498 polymorphic genotypes of ICAM-1 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with ICAM-1 variants in carcinogenesis of UCC in Taiwan.
Assuntos
Predisposição Genética para Doença , Molécula 1 de Adesão Intercelular/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Idoso , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Risco , Taiwan , Neoplasias da Bexiga Urinária/etiologiaRESUMO
The aim of this study was to examine the plasma level changes of soluble Axl (sAxl) prior to and following treatment with antibiotics in hospitalized adult patients with community-acquired pneumonia (CAP), and to investigate the correlating clinical and laboratory manifestations of CAP with plasma sAxl levels. Blood samples were obtained from 61 adult CAP patients (prior to and following treatment with antibiotics) and 60 healthy controls in order to measure the plasma concentrations of sAxl using the enzyme-linked immunosorbent assay. The plasma-soluble Axl concentration level was markedly elevated in patients with CAP prior to treatment, compared with the controls, and decreased markedly following treatment. The levels of white blood cells, neutrophils, and C-reactive protein decreased markedly following treatment with antibiotics and did not correlate with the concentration level of sAxl. However, the plasma concentration of sAxl correlated with the severity of CAP with the pneumonia severity index score (r=0.350, P=0.006, n=61), the CURB-65 score (r=0.281, P=0.028, n=61) and the acute physiology and chronic health evaluation II score (r=0.313, P=0.014, n=61). In conclusion, plasma sAxl may be involved in the clinical assessment of the severity of CAP, which may guide the development of treatment strategies and predict the clinical outcome.
Assuntos
Infecções Comunitárias Adquiridas/sangue , Pneumonia/sangue , Proteínas Proto-Oncogênicas/sangue , Receptores Proteína Tirosina Quinases/sangue , Índice de Gravidade de Doença , APACHE , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Demografia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Solubilidade , Receptor Tirosina Quinase AxlRESUMO
BACKGROUND: Vascular endothelial growth factor C (VEGF-C), an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies including hepatocellular carcinoma (HCC). The purpose of this study was to examine whether VEGF-C gene polymorphisms are associated with susceptibility to HCC and its clinicopathological development. METHODS: Genetic polymorphisms of VEGF-C of 135 patients with HCC and 520 noncancer controls were analyzed by a real-time polymerase chain reaction (PCR). RESULTS: We found that a significantly (P = 0.021) higher risk for HCC was shown in individuals with the VEGF-C rs1485766 A/A genotype compared to those with wild-type homozygotes; a high frequency of an advanced stage and a low frequency of being positive for cirrhosis were respectively shown in HCC patients with the VEGF-C rs7664413 CT/TT and rs3775194 GC/CC genotypes. Moreover, we found that the GGACA, GACTG, CGATG, and GGCTG haplotypes of five VEGF-C single-nucleotide polymorphisms (SNPs) combined were also related to the risk of HCC. CONCLUSIONS: Our results suggest that the VEGF-C rs1485766 SNP and either of five haplotypes combined might contribute to a prediction of susceptibility to HCC. The genetic polymorphism of VEGF-C rs7664413 might be a predictive factor for advanced-stage HCC.
Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Fator C de Crescimento do Endotélio Vascular/genética , Adulto , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , TaiwanRESUMO
Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Chalconas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase 4/metabolismo , NF-kappa B/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Ativação Enzimática/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Ligação Proteica , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
Plasma YKL-40 level has been reported as playing a significant role in community-acquired pneumonia (CAP). However, the correlation between plasma level of YKL-40 and the severity of CAP has not been reported. This study identifies the relationship between plasma level changes of the YKL-40 gene in adult patients hospitalized with CAP. The ELISA was used to measure the plasma YKL-40 level from 61 adult CAP patients before and after antibiotic treatment and from 60 healthy controls. The plasma YKL-40 levels were significantly increased in patients with CAP compared to normal controls. Moreover, the plasma concentration of YKL-40 correlated with the severity of CAP based on the pneumonia severity index (PSI) score (r = 0.630, p < 0.001), the CURB-65 (confusion, uremia, respiratory rate, BP, age 65 years) score (r = 0.640, p < 0.001), the Acute Physiology And Chronic Health Evaluation II (APACHE II) score (r = 0.539, p < 0.001) and length of hospital stay (r = 0.321, p = 0.011), respectively. In conclusion, plasma YKL-40 may play a role in the diagnosis and clinical assessment of CAP severity, which could potentially guide the development of treatment strategies.
Assuntos
Adipocinas/sangue , Infecções Comunitárias Adquiridas/sangue , Lectinas/sangue , Pneumonia/sangue , APACHE , Proteína 1 Semelhante à Quitinase-3 , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico , Pneumonia/patologiaRESUMO
Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Catecóis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Agaricales/química , Animais , Caspase 3/genética , Caspase 8/genética , Caspase 9/genética , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Camundongos , Camundongos SCID , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
BACKGROUND: The enhancer of zeste 2 (EZH2) gene encodes the histone methyltransferase that is the catalytic component of the polycomb repressive complex-2, which initiates epigenetic silencing of genes. The expression level of EZH2 in hepatocellular carcinoma (HCC) is highly correlated with tumor progression; however, it has not been determined if specific EZH2 genetic variants are associated with the risk of HCC. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with HCC susceptibility and its clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: A total of 220 HCC patients and 552 cancer-free controls were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, the individuals carrying at least one C allele at EZH2 rs6950683 and rs3757441 had a 0.611-fold and a 0.660-fold lower risk of developing HCC than did wild-type (TT) carriers, respectively. The CCCA or CCTA haplotype among the four EZH2 sites (rs6950683, rs2302427, rs3757441, and rs41277434), respectively, was also associated with a reduced risk of HCC. Furthermore, HCC patients who carried at least one C allele at rs6950683 or rs3757441 had a higher lymph-node-metastasis risk but a lower liver-cirrhosis risk than did patients carrying the wild-type allele. CONCLUSIONS: The rs6950683 and rs3757441 polymorphic genotypes of EZH2 might contribute to the prediction of susceptibility to and pathological development of HCC. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of HCC in Taiwan.
Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Complexo Repressor Polycomb 2/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Consumo de Bebidas Alcoólicas , Alelos , Estudos de Casos e Controles , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Variação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Reação em Cadeia da Polimerase em Tempo Real , FumarRESUMO
BACKGROUND: The aim of this study was to investigate the differential plasma levels of lipocalin 2 (LCN2) and its complex with MMP-9 (where MMP is matrix metalloproteinase) before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). METHOD: Plasma LCN2 and LCN2/MMP-9 complex levels were measured in 61 adult patients with CAP and 60 healthy controls using commercial enzyme-linked immunosorbent assay (ELISA). RESULTS: A decrease in the number of white blood cells (WBCs) and neutrophils and decreases in the levels of C-reactive protein (CRP), LCN2, and LCN2/MMP-9 complex were observed after antibiotic treatment. The plasma level of LCN2, but not that of CRP, was correlated with the severity of CAP based on the Pneumonia Severity Index (PSI; r = 0.333, P = 0.009), confusion, urea, respiratory rate and blood pressure (CURB)-65 (r = 0.288, P = 0.024), and Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (r = 0.328, P = 0.010). LCN2 levels were also significantly correlated with LCN2/MMP-9 levels and the numbers of WBCs or neutrophils. CONCLUSIONS: Plasma levels of LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP. Plasma LCN2 might play a further role in the clinical assessment of the severity of CAP, which could potentially guide the development of future treatment strategies.
Assuntos
Infecções Comunitárias Adquiridas/sangue , Lipocalinas/sangue , Pneumonia/sangue , Proteínas Proto-Oncogênicas/sangue , APACHE , Proteínas de Fase Aguda , Adulto , Idoso , Antibacterianos/uso terapêutico , Proteína C-Reativa/análise , Infecções Comunitárias Adquiridas/tratamento farmacológico , Feminino , Humanos , Contagem de Leucócitos , Lipocalina-2 , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Neutrófilos , Pneumonia/tratamento farmacológico , Índice de Gravidade de Doença , TaiwanRESUMO
A 67-year-old woman presented with a history of dilated cardiomyopathy with congestive heart failure since 2003, who subsequently developed lower rectal cancer (adenocarcinoma) with liver, bone, and lymph node metastasis. Abdominoperineal resection and hepatectomy were performed. The patient received two rounds of intravenous chemotherapy, including 12 and six courses of FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin; 85 mg/m(2) per cycle). She underwent a third round of intravenous FOLFOX4 because of tumor progression. During the 21(st) course of FOLFOX4 regimen, the patient developed ST segment depression in lead II and prolongation of QT interval with polymorphic ventricular tachycardia, torsades de pointes right after the start of oxaliplatin infusion. Immediate defibrillation and cardiopulmonary resuscitation were administered, and the patient regained spontaneous circulation and consciousness. Twelve-lead electrocardiogram showed ST segment elevation in III, aVF, and ST segment depression in V4-6 after resuscitation. To our knowledge, prolongation of QT interval with torsades de pointes and coronary spasm with myocardial injury that were stabilized in one patient following oxaliplatin infusion has not been reported. We present a patient with these rare complications.