RESUMO
BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.
Assuntos
Anilidas , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Camundongos Nus , Piridinas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X , Animais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Anilidas/farmacologia , Anilidas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Proteína bcl-X/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos Endogâmicos BALB C , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MasculinoRESUMO
Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Neoplasias Gástricas , Humanos , Filogenia , Microdissecção , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , GenômicaRESUMO
INTRODUCTION: This study aimed to develop a prognostic nomogram for patients with gastric cancer (GC) based on the levels of programmed death 1 ligand 1 (PDL1) and carcinoembryonic antigen (CEA). METHODS: The nomogram was developed using data from a primary cohort of 247 patients who had been clinicopathologically diagnosed with GC, as well as a validation cohort of 63 patients. Furthermore, the nomogram divided the patients into three different risk groups for overall survival (OS)-the low-risk, middle-risk, and high-risk groups. Univariate and multivariate Cox hazard analyses were used to determine all of the factors included in the model. Decision curve analysis and receiver operating characteristic (ROC) curves were used to assess the accuracy of the nomogram. RESULTS: The Kaplan-Meier survival analysis revealed that metastasis stage, clinical stage, and CEA and PDL1 levels were predictors for progress-free survival (PFS) and OS of patients with GC. Metastasis stage, clinical stage, and CEA and PDL1 levels were found to be independent risk factors for the PFS and OS of patients with GC in a multivariate analysis, and the nomogram was based on these factors. The concordance index of the nomogram was 0.763 [95% confidence interval (CI) 0.740-0.787]. The area under the concentration-time curve of the nomogram model was 0.81 (95% CI 0.780-0.900). According to the decision curve analysis and ROC curves, the nomogram model had a higher overall net efficiency in forecasting OS than clinical stage, CEA and PDL1 levels. CONCLUSION: In conclusion, we proposed a novel nomogram that integrated PDL1 and CEA, and the proposed nomogram provided more accurate and useful prognostic predictions for patients with GC.
Assuntos
Nomogramas , Neoplasias Gástricas , Humanos , Antígeno Carcinoembrionário , Ligantes , PrognósticoRESUMO
Colon cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2-like kinase 1(CLK1), CLK2, and A-kinase anchor protein 8-like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low-risk group, and TME-related pathway gene expression was also higher in low-risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.
Assuntos
Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Neoplasias do Colo/genética , Expressão Gênica , Humanos , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Prognóstico , Splicing de RNA/genética , Fatores de Processamento de RNA/genética , RNA Mensageiro/genética , Microambiente TumoralRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. METHODS: The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson's chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan-Meier survival curve was used for survival analysis. RESULTS: We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan-Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001). CONCLUSIONS: In conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.
RESUMO
Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy's potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine's ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Janus Quinase 2/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Piperidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Modelos Biológicos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Piperidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Proteína bcl-X/metabolismo , GencitabinaRESUMO
BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.
Assuntos
Biomarcadores , Neoplasias do Colo/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Microambiente Tumoral/fisiologia , Neoplasias do Colo/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer in China, with poor prognosis and lack of effective targeted therapy. It has been reported that ibrutinib possesses anticancer activity in ESCC with MYC and/or ERBB2 amplification. Here we explored the synergistic antitumor effect of a novel multi-kinase inhibitor APG-2449 with ibrutinib in ESCC and clarified the mechanism of the combination effect through in vitro and in vivo experiment. We found that APG-2449 exerted antitumor effect in ESCC. APG-2449 combined with ibrutinib showed synergistic inhibition of cell viability in ESCC cell lines. APG-2449 combined with ibrutinib dramatically inhibited the proliferation and migration of ESCC cells. Furthermore, we observed that ibrutinib combined with APG-2449 could induce more cancer cells arrested in the G1/S phase and apoptosis. In terms of mechanism, ibrutinib alone could decrease the phosphorylation level of EGFR and its downstream pathway of MEK/ERK. The combination therapy of APG-2449 and ibrutinib could significantly down-regulate the phosphorylation level of MEK/ERK and AKT. In ESCC xenotransplantation models, single therapy with either ibrutinib or APG-2449 was equivalent in delaying tumor growth, while the combination therapy suppressed tumor growth more significantly. Our data strongly suggest that the combination therapy of APG-2449 and ibrutinib can provide an effective therapeutic strategy for ESCC patients, which deserved further clinical investigation.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/administração & dosagem , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Adenina/administração & dosagem , Adenina/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Quinase 1 de Adesão Focal/antagonistas & inibidores , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Piperidinas/química , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: The mechanism of PD-L1 expression in gastric cancer patients remains unclear. microRNAs (miRs) have been reported to be crucial components of the crosstalk between tumor-immune cells and emerging evidence suggests that microRNA-375 (miR-375) is significantly downregulated in digestive system tumors, but its association with PD-L1 expression in gastric cancer remains to be determined. METHODS: The expression level of miR-375 was first investigated in human gastric cancer tissues and cell lines. Its effect on gastric cancer cell proliferation, migration, invasion, and apoptosis were evaluated in vitro via CCK8, colony formation assays, wound healing assays, transwell assays, and flow cytometry. In vivo experiments using immunodeficient BALB/c nude female mice were also performed. Luciferase reporter assays were employed to identify interactions between miR-375 and its target genes. RESULTS: Quantitative real-time PCR showed that the expression of miR-375 was negatively correlated with PD-L1 in gastric cancer tissues. The overexpression of miR-375 inhibited gastric cancer cell proliferation, migration, invasion, and the knockdown of miR-375 demonstrated opposite effects, both in vitro and in vivo. Luciferase reporter assays showed that miR-375 could bind to the 3'-UTR regions of JAK2 and an inverse association between miR-375 and JAK2/STAT3/PD-L1 expression in gastric cancer cell lines was also observed. In vivo experiments showed that miR-375-overexpression decreased the growth of xenograft tumors in immunodeficient BALB/c mice. CONCLUSIONS: miR-375 negatively regulates PD-L1 expression in gastric cancer via the JAK2/STAT3 signaling pathway and could be a promising novel therapeutic target in gastric cancer.
Assuntos
Antígeno B7-H1 , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Gástricas , Animais , Antígeno B7-H1/metabolismo , Feminino , Janus Quinase 2/metabolismo , Luciferases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
Background: Increasing evidences from phase II or III trials have proved that salvage systematic therapy, including chemotherapy, target therapy, or checkpoint inhibitor therapy can prolong survival in patients who do not succeed with second line therapy, yet there are no guidelines for the optimum third-line treatments. To compare the effectiveness and safety of current third-line therapies for metastatic Gastric Cancer (mGC), we conducted this network analysis. Methods: Literature up to Sep 30, 2019 were systematically searched and analyzed by a Bayesian fixed-effect model. Results: This study included seven randomized clinical trails which involved 2,655 patients. It turns out that for overall survival, nivolumab has the highest probability to be the optimal choice for overall survival (OS). For patients with no peritoneal metastases, the network meta-analysis showed that Nivolumab (HR:0.64; 95% CI: 0.48-0.85) and Trifluridine/tipiacil (HR:0.66; 95% CI: 0.51-0.86) were associated with significantly higher improvement in OS than placebo. However, patients with peritoneal metastases could not benefit from nivolumab, ramucirumab, or Trifluridine/tipiacil, when compared with a placebo. For progression-free survival, apatinib (850 mg) was the most likely candidate, followed by ramucirumab. Statistically, Apatinib (850 mg), Trifluridine/tipiacil, and SLC had higher incidences of high-grade adverse events (AEs) than placebo. Conclusion: Our findings demonstrate that nivolumab has the best balance between acceptability and effectiveness in the third line therapy for mGC.
RESUMO
BACKGROUND AND OBJECTIVE: Noninvasive prognostic tools for colorectal cancer (CRC) are urgently needed. This study was designed to investigate the prognostic value of preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels retrospectively in CRC patients. METHODS: Preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels were analyzed retrospectively in 250 patients with CRC. The prognostic significance of these indexes was determined by univariate and multivariate Cox hazard models. RESULTS: CRC patients with higher levels of ApoA-I and HDL-C and lower levels of CRP had significantly longer overall survival (OS, log rank test, p<0.05). Based on univariate analysis, ApoA-I levels (p=0.002), CRP levels (p=0.007), HDL-C levels (p=0.005), pT classification (p=0.005), pN classification (p<0.001), pM classification (p<0.001) and pTNM stage (p<0.001) were significantly associated with OS. Multivariate Cox proportional hazards regression analysis indicated that ApoA-I levels (HR: 1.52, p=0.023), CRP levels (HR: 1.85, p=0.035) and pTNM stage (HR: 2.53, p< 0.001) were independent predictors of CRC survival. The included patients were then stratified into three tiers based on the ApoA-I and CRP levels. In the whole cohort, the OS and disease-free survival differed significantly between the low-risk (ApoA-I≥1.08 mg/dL and CRP<3.04 mg/dL), medium-risk (ApoA-I≥1.08 mg/dL or CRP<3.04 mg/dL), and high-risk (ApoA-I<1.08 mg/dL and CRP ≥3.04 mg/dL) groups (p=0.001 and p=0.004). CONCLUSION: Decreased levels of ApoA-I and HDL-C and increased levels of CRP were predictive of poor prognosis among patients with CRC. In addition, the combination of ApoA-I and CRP can serve as a novel prognostic stratification system for more accurate clinical staging of CRC.
RESUMO
BACKGROUND: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. METHODS: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. RESULTS: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. CONCLUSIONS: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Células Jurkat , Masculino , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In the publication of this article [1], there was an error in Figs. 2, 3 and 6.
RESUMO
BACKGROUND: Ovarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer. METHODS: CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescenceâmicroscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation. RESULTS: APG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts. CONCLUSIONS: Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer.
RESUMO
OBJECTIVE: To measure the rate of high-risk group and the detection rate of colorectal cancer (CRC) in communities in Guangdong province and to provide scientific rationales for formulating mass screening plans in high-risk group. METHODS: Mass survey was conducted by questionnaire combined fecal occult blood test (FOBT) in Huizhou region, Guangdong Province, to sort out the high-risk population of CRC. Then the high-risk population was screened by colonoscopy and pathology to identify CRC. The differences were compared by direct expenditure which was used to calculate screening cost. RESULTS: A total of 68,953 people were surveyed. There were 940 people in high-risk group (detection rate: 1.36%), 3118 in immunity FOBT positive group (detection rate: 4.52%), Merging aforementioned two groups, there were 3870 in population at risk (detection rate: 5.61%). The CRC detection rate in high-risk group, immunity FOBT positive group, population at risk and average-risk group was 506.3/10(5), 314.3/10(5), 315.9/10(5) and 17.7/10(5) respectively. The positive predictive value of CRC screening scheme by high-risk group questionnaire-colonoscopy was 0.43% while CRC screening scheme by FOBT-colonoscopy 0.22%. In terms of direct expenditure of CRC per case in high-risk group and immunity FOBT positive group was 47,834.5 yuan and 82,303.6 yuan. The latter was 1.7 times than that of the former. CONCLUSIONS: The scheme of questionnaire combined FOBT for CRC is an effective way in mass survey. The scheme by high-risk group questionnaire-colonoscopy has a much better cost-effectiveness than that of the scheme by FOBT-colonoscopy so that it should be one of the preferred methods for individual screening in high-risk group.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Programas de Rastreamento/economia , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Custo-Benefício , Humanos , Lactente , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To explore the epidemiology characteristics of colorectal cancer on community group in Guangdong province. METHODS: Huidong was took as the research spot to investigate the sickness and incidence of colorectal cancer among a whole community group in Guangdong province, and two projects were used simultaneously: "screening of colorectal cancer in high risk group" and "screening project using fecal occult blood test". The numeration time for population of 10 towns was set at July 1, 2005. Five towns were sampled out from Huidong with 100,859 persons. Meanwhile, the diseases and death cause registering system was established. RESULTS: The incidence of colorectal cancer in Huidong community group was 15.2/100,000 (male 17.2/100,000, female 13.0/100,000), the age-adjusted incidence was 17.6/100,000 (male 19.5/100,000, female 16.7/100,000). The morbidity was 41.9/100,000 (male 46.5/100,000, female 37.2/100,000), the age-adjusted morbidity was 49.0/100,000 (male 54.1/100,000, female 45.6/100,000). The mortality was 5.0/100,000 (male 5.9/100,000, female 4.0/100,000) and the age-adjusted morbidity was 6.4/100,000 (male 7.2/100,000, female 5.7/100,000). CONCLUSION: The incidence of colorectal cancer in Huidong community group is lower than that of high incidence area in China, but gets close to the normal incidence area of China and general level of the world.