RESUMEN
BACKGROUND: Anaemia is highly prevalent in gastric cancer (GC) patients. The role of initial haemoglobin levels in predicting the prognosis of GC patients treated by chemotherapy has not been well determined. Our present study aims to evaluate the relationship between the degree of anaemia and the overall survival (OS) and progression-free survival (PFS) of patients with GC. METHODS: Our retrospective study enrolled 598 patients who were treated with chemotherapy when the recurrent or metastatic GCs were unsuitable for surgical resection. Univariate and multivariate analyses were performed to identify risk factors that had the potential to affect patient prognosis. Additionally, the relationship between clinicopathological characteristics, including treatment method, and degree of cancer-related reduction in haemoglobin was further analysed. RESULTS: Our results revealed that patients with HBini level ≤ 80 g/L had a trend toward a shortened median OS and PFS (p = 0.009 and p = 0.049, respectively). Interestingly, we also found that HBdec ≥ 30 g/L was associated with a significantly shortened median OS and PFS (p = 0.039 and p = 0.001, respectively). Multivariate analysis showed that HBini levels ≤80 g/L could be used as an independent prognostic factor for recurrent and metastatic GC. More importantly, HBdec ≥ 30 g/L and treatment response were also significantly associated with OS and PFS. Furthermore, the degree of haemoglobin decrease was associated with chemotherapy including platinum and the number of chemotherapy cycles. CONCLUSION: Our study concludes that the initial degree of anaemia and a decrease in haemoglobin of ≥30 g/L can serve as biomarkers to predict prognosis in recurrent or metastatic GC patients, while chemotherapy treatment rather than red blood cell (RBC) transfusion can improve their prognosis. Additionally, platinum should not be recommended for treating severely anaemic GC patients.
Asunto(s)
Anemia/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Hemoglobinas/análisis , Modelos Estadísticos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Anciano , Anemia/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Masculino , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1α instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Indoles/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Animales , Línea Celular Tumoral , Glioblastoma/patología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neovascularización Patológica/patología , Panobinostat , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Our study observed the relationship between transient receptor potential melastatin 7 (TRPM7) expression and the metastatic process of nasopharyngeal carcinoma (NPC). We found that TRPM7 was overexpressed in 102 out of 206 (49.5%) human NPC cases and was significantly associated with clinical stage and lymphatic and distant metastasis. The results suggested that TRPM7 promotes NPC cell migration and invasion in vitro. Further, TRPM7 was correlated with poor clinical outcome and was an independent predictor for 5-year overall survival rate (HR, 1.832; 95% CI, 1.237-4.146 [P = 0.041]). In conclusion, TRPM7 promotes the metastasis of NPC and may serve as a prognostic marker in NPC patients.
Asunto(s)
Movimiento Celular , Neoplasias Nasofaríngeas/secundario , Nasofaringe/metabolismo , Canales Catiónicos TRPM/metabolismo , Western Blotting , Carcinoma , Proliferación Celular , Células Cultivadas , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Nasofaringe/patología , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Serina-Treonina Quinasas , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/genéticaRESUMEN
Type 2 diabetes mellitus (T2DM) has contributed to advanced breast cancer development over the past decades. However, the mechanism underlying this contribution is poorly understood. In this study, we determined that high glucose enhanced proteasome activity was accompanied by enhanced proliferation, migration and invasion, as well as suppressed apoptosis, in human breast cancer MCF-7 cells. Proteasome inhibitor bortezomib (BZM) pretreatment mitigated high glucose-induced MCF-7 cell growth and invasion. Furthermore, high glucose increased protein kinase C delta (PKC?)-phosphorylation. Administration of the specific PKC? inhibitor rottlerin attenuated high glucose-stimulated cancer cell growth and invasion. In addition, PKC? inhibition by both rottlerin and PKC? shRNA significantly suppressed high glucose-induced proteasome activity. Our results suggest that PKC?-dependent ubiquitin proteasome system activation plays an important role in high glucose- induced breast cancer cell growth and metastasis.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glucosa/farmacología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Proteína Quinasa C-delta/metabolismo , Ubiquitina/metabolismo , Acetofenonas/farmacología , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Glucosa/metabolismo , Humanos , Células MCF-7 , Fosforilación/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Proteína Quinasa C-delta/antagonistas & inhibidores , Pirazinas/farmacologíaRESUMEN
BACKGROUND & OBJECTIVE: Accumulating evidences showed that the overexpression of multidrug resistance-associated protein 2 (MRP2) was the main cause of multidrug resistance in hepatocellular carcinoma (HCC); and the methylated cytosine at cytosine-guanine (CpG) dinucleotides might silence the gene expression. This study was to evaluate the inhibiting effect of methylated oligonucleotide (MON) on MRP2 gene transcription. METHODS: MON complementary to human MRP2 promoter region was designed. The non- methylated oligonucleotide (NON) carried same nucleotide acid sequence with MON, but the cytosines were not methylated. Cells from human HCC cell line HepG2 were divided into 3 groups: control group, NON group, and MON group. HepG2 cells were transfected with liposome-encapsulated oligonucleotide, cytotoxicity was determined by MTT assay. Reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry (FCM) were used to analyze the expression of MRP2. RESULTS: MON specifically inhibited MRP2 gene transcription and down-regulated the expression of MRP2 in a concentration- dependent manner in vitro, whereas NON had no effect. The positive rates of MRP2 protein were 18.0%, 9.15%, 5.73%, 3.73%, and 2.56% respectively after transfected with 1, 2, 4, 8, and 16 micromol/L MON. It was 24.5% in NON group. The 50% inhibitory concentration (IC50) of epirubicin, hydroxyl- camptothecin, and carboplatin were reduced in MON group. CONCLUSIONS: MON can inhibit MRP2 gene transcription, enhance chemosensitivity, and reverse multidrug resistance of HCC cells,it may become a new gene therapeutic agent for HCC.