RESUMO
BACKGROUND AND AIMS: Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and impacting tumorigenesis remains elusive. APPROACH AND RESULTS: Transcriptomic and metabolomic analyses of purine biosynthesis and purine degradation pathways were performed in the tumor and associated nontumor liver tissues obtained from 62 patients with HCC, one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated, while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DNA damage repairing (DDR) machinery through upregulating RNA N6-methyladenosine (m 6 A) modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in 5 independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo . CONCLUSIONS: Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Purinas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Dano ao DNA/genética , Reparo do DNA/genética , Epigênese Genética/genética , Regulação da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Purinas/metabolismoRESUMO
Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiation therapy (RT)-mediated anticancer effects has not yet been explored. We investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assays, we found that RT-induced proliferative inhibition was critically associated with SET expression. We next tested a novel SET antagonist, N4-(3-ethynylphenyl)-6,7-dimethoxy-N2-(4-phenoxyphenyl) quinazoline-2,4-diamine (EMQA), in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared with mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore protein phosphatase 2A-mediated phospho-Akt (p-AKT) downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach.
Assuntos
Carcinoma Hepatocelular/radioterapia , Regulação para Baixo/efeitos dos fármacos , Chaperonas de Histonas/antagonistas & inibidores , Neoplasias Hepáticas/radioterapia , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Regulação para Baixo/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.
Assuntos
Leucemia/tratamento farmacológico , Oligopeptídeos/farmacologia , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Cicloeximida/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HL-60 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células K562 , Leucemia/fisiopatologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias/métodos , Ácido Okadáico/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
UNLABELLED: The effective therapeutic targets for hepatocellular carcinoma remain limited. Pituitary homeobox 1 (PITX1) functions as a tumor suppressor in hepatocarcinogenesis by regulating the expression level of Ras guanosine triphosphatase-activating protein. Here, we report that protein tyrosine phosphatases 1B (PTP1B) directly dephosphorylated PITX1 at Y160, Y175, and Y179 to further weaken the protein stability of PITX. The PTP1B-dependent decline of PITX1 reduced its transcriptional activity for p120RasGAP (RASA1), a Ras guanosine triphosphatase-activating protein. Both silencing of PTP1B and PTP1B inhibitor up-regulated the PITX1-p120RasGAP axis through hyperphosphorylation of PITX1. Sorafenib, the first and only targeted drug approved for hepatocellular carcinoma, directly decreased PTP1B activity and promoted the expression of PITX1 and p120RasGAP by PITX1 hyperphosphorylation. Molecular docking also supported the potential interaction between PTP1B and sorafenib. PTP1B overexpression impaired the sensitivity of sorafenib in vitro and in vivo, implying that PTP1B has a significant effect on sorafenib-induced apoptosis. In sorafenib-treated tumor samples, we further found inhibition of PTP1B activity and up-regulation of the PITX1-p120RasGAP axis, suggesting that PTP1B inhibitor may be effective for the treatment of hepatocellular carcinoma. By immunohistochemical staining of hepatic tumor tissue from 155 patients, the expression of PTP1B was significantly in tumor parts higher than nontumor parts (P = 0.02). Furthermore, high expression of PTP1B was significantly associated with poor tumor differentiation (P = 0.031). CONCLUSION: PTP1B dephosphorylates PITX1 to weaken its protein stability and the transcriptional activity for p120RasGAP gene expression and acts as a determinant of the sorafenib-mediated drug effect; targeting the PITX1-p120RasGAP axis with a PTP1B inhibitor may provide a new therapy for patients with hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Proteína p120 Ativadora de GTPase/genética , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Modelos Moleculares , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Fosforilação , SorafenibeRESUMO
BACKGROUND: Enumerating hematopoietic progenitor cells (HPCs) by using an automated hematology analyzer is a rapid, inexpensive, and simple method for predicting a successful harvest compared with enumerating circulating CD34+ cells. However, the optimal HPC cutoff count and the indicating factors to be considered for improved predicting have not yet been determined. STUDY DESIGN AND METHODS: Between 2007 and 2012, a total of 189 consecutive patients who proceeded to peripheral blood stem cell (PBSC) harvesting were retrospectively recruited. Baseline characteristics were analyzed to identify the risk factors for a failed harvest, which were defined as less than 2 × 10(6) CD34+ cells/kg. Variables identified by multivariate logistic regression and correlation analysis for predicting a successful harvest were subjected to classification and regression tree (CART) analysis. RESULTS: PBSCs were successfully harvested in 154 (81.5%) patients. An age of at least 60 years, a diagnosis of a solid tumor, at least five prior chemotherapy cycles, prior radiotherapy, and mobilization with granulocyte-colony-stimulating factor alone or high-dose cyclophosphamide were independent baseline predictors of poor mobilization. In CART analysis, patients with zero to two host risk factors and either higher HPC (≥28 × 10(6) /L) or mononuclear cell (MNC; ≥3.5 × 10(9) /L) counts were categorized as good mobilizers and their harvest success rate was 92.3%. By contrast, 30.3% of harvests were adequate in the patients with three to five host risk factors and lower HPC and MNC counts. CONCLUSION: A CART algorithm incorporating host predictors and HPC and MNC counts improves predictions in a successful harvest and might reduce the necessity of monitoring peripheral CD34+ cells.
Assuntos
Algoritmos , Árvores de Decisões , Mobilização de Células-Tronco Hematopoéticas/métodos , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Feminino , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/terapia , Células-Tronco de Sangue Periférico/imunologia , Células-Tronco de Sangue Periférico/metabolismo , Estudos RetrospectivosRESUMO
The relationship between chronic myeloid leukemia (CML) and tuberculosis (TB) has not been determined. We conducted a national survey including 1,082 CML patients identified from the Taiwan National Health Insurance database covering a period between 1998 and 2011; the matched non-exposed cohort included 10,820 subjects without CML that were matched for age, sex and comorbidities. The impact of TB was measured by the overall mortality, and the risk factors were identified by a multivariate Cox proportional hazards model. We found the risk of TB was higher in the CML cohort, with an adjusted hazard ratio (aHR) of 3.76 (p = 0.001) for both pulmonary (aHR 3.23, p < 0.001) and extrapulmonary (aHR 9.77, p = 0.001) TB. Specific risk factors were: aged ≥ 60 (aHR 3.24, p = 0.022), being male (aHR 13.49, p = 0.012), receiving stem cell transplantation (aHR 10.50, p = 0.001) and interferon-α therapy (aHR 3.34, p = 0.011). CML patients with TB had a higher mortality rate than those without (aHR 2.04, p = 0.043). We conclude that the incidence of TB is significantly higher in CML patients of male sex, aged ≥ 60, having received either stem cell transplantation or interferon-α treatment. Careful screening strategies for TB should be considered for CML patients with high risk of the infection.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Tuberculose/epidemiologia , Tuberculose/etiologia , Adulto , Comorbidade , Feminino , Humanos , Incidência , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Fatores de Risco , Taiwan , Tuberculose/mortalidadeRESUMO
BACKGROUND: This study identified possible risk factors for newly diagnosed mood disorders, including depressive and bipolar disorders, in prostate cancer patients. METHODS: From 2000 to 2006, two cohorts were evaluated on the occurrence of mood disorder diagnosis and treatment. For the first cohort, data of patients diagnosed with prostate cancer was obtained from the Taiwan National Health Insurance (NHI) Research Database. As the second cohort, a cancer-free comparison group was matched for age, comorbidities, geographic region, and socioeconomic status. RESULTS: Final analyses involved 12,872 men with prostate cancer and 12,872 matched patients. Increased incidence of both depressive (IRR 1.52, 95% CI 1.30-1.79, P <0.001) and bipolar disorder (IRR 1.84, 95% CI 1.25-2.74, P = 0.001) was observed among patients diagnosed with prostate cancer. Multivariate matched regression models show that cerebrovascular disease (CVD) and radiotherapy treatment could be independent risk factors for developing subsequent depressive and bipolar disorders. CONCLUSION: We observed that the risk of developing newly diagnosed depressive and bipolar disorders is higher among Taiwanese prostate cancer patients. Clinicians should be aware of the possibility of increased depressive and bipolar disorders among prostate cancer patients in Taiwan. A prospective study is necessary to confirm these findings.
Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Depressivo/epidemiologia , Neoplasias da Próstata/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Classe Social , Taiwan/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism. METHODS: In total, five ER-negative breast cancer cell lines (HCC-1937, MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3) were used for in vitro studies. Cellular apoptosis was examined by flow cytometry and Western blot analysis. Signal transduction pathways in cells were assessed by Western blot analysis. The in vivo efficacy of tamoxifen was tested in xenograft nude mice. RESULTS: Tamoxifen induced significant apoptosis in MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3 cells, but not in HCC-1937 cells. Tamoxifen-induced apoptosis was associated with inhibition of cancerous inhibitor of protein phosphatase 2A (CIP2A) and phospho-Akt (p-Akt) in a dose-dependent manner. Ectopic expression of either CIP2A or Akt protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, tamoxifen increased protein phosphatase 2A (PP2A) activity, and tamoxifen-induced apoptosis was attenuated by the PP2A antagonist okadaic acid in the sensitive cell lines, but not in resistant HCC-1937 cells. Moreover, silencing CIP2A by small interfering RNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Furthermore, tamoxifen regulated CIP2A protein expression by downregulating CIP2A mRNA. Importantly, tamoxifen inhibited the in vivo growth of MDA-MB-468 xenograft tumors in association with CIP2A downregulation, whereas tamoxifen had no significant effect on CIP2A expression and anti-tumor growth in HCC-1937 tumors. CONCLUSIONS: Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. Our data suggest a novel "off-target" mechanism of tamoxifen and suggest that CIP2A/PP2A/p-Akt signaling may be a feasible anti-cancer pathway.
Assuntos
Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Autoantígenos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tamoxifeno/farmacologia , Idoso , Animais , Autoantígenos/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Pessoa de Meia-Idade , Receptores de Estrogênio/metabolismo , Transcrição Gênica , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study is aimed to evaluate the cancer risk among patients with coal workers' pneumoconiosis (CWP) using a nationwide population-based dataset. Patients without previous cancer who had been diagnosed with CWP and followed-up for more than 1 year between 1997 and 2006 were recruited from the Taiwan National Health Insurance database. Standardized incidence ratios (SIRs) of cancers in CWP patients were calculated and compared to the cancer incidence in the general population. Risk factors for cancer development were also analyzed. After a median follow-up of 9.68 years, 954 cancers developed among 8,051 recruited CWP patients, with a follow-up of 69,398 person-years. The SIR for all cancers was 1.12 [95% confidence interval (CI) 1.04-1.18]. Males older than 80 years had a SIR of 1.27 (95% CI: 1.06-1.51). The SIRs of esophageal (1.76, 95% CI: 1.24-2.44), gastric (1.42, 95% CI: 1.13-1.76), liver and biliary tract (1.18, 95% CI: 1.01-1.37) and lung and mediastinal (1.45, 95% CI: 1.26-1.66) cancers were significantly higher in the CWP group than in the general population. Multivariate analysis showed that age ≥ 60 years [hazard ratio (HR) 1.70, 95% CI: 1.41-2.05), male gender (HR = 1.79, 95% CI: 1.44-2.23) and liver cirrhosis (HR = 3.99, 95% CI: 2.89-5.51) were significant predictors of cancer development in patients with CWP. We concluded that patients with CWP, especially elderly males, were at increased risk of cancer. Age, male gender and liver cirrhosis were independent risk factors for cancer development.
Assuntos
Antracose/epidemiologia , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Minas de Carvão , Feminino , Humanos , Incidência , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taiwan/epidemiologia , Adulto JovemRESUMO
Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and drug mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Expressão Gênica , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Pirróis/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Pirróis/administração & dosagem , Fatores de Transcrição de Fator Regulador X , Fator Regulador X1 , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several revisions of International Prognostic Index (IPI) have been proposed for patients with diffuse large B-cell lymphoma (DLBCL) after the introduction of rituximab. Expanding evidence suggests that baseline absolute lymphocyte count (ALC) is also an independent factor for outcome prediction. We investigated the optimal prognostic model for these patients in the rituximab era. The study enrolled 274 consecutive patients with DLBCL receiving first-line cyclophosphamide, doxorubicin, vincristine, and prednisone based chemotherapy with rituximab between 2003 and 2009. Five factors within IPI and ALC were entered for Cox regression analysis. Overall survival (OS) and progression-free survival were calculated for different risk groups of models. Efficacy of models was compared by the value of Akaike information criterion (AIC). Revised IPI (R-IPI) and ALC/R-IPI, but not IPI, were informative to discriminate between different risk groups. In multivariate analysis for individual factors of the prognostic models, performance status >1 [odds ratio (OR) 3.59], Ann Arbor stage III or IV (OR 2.24), and ALC <1 × 109/L (OR, 2.75) remained significant. Another modified score based on the three factors divided patients into four risk groups and the 3-year OS rate was 93, 77, 39, and 13 %, respectively. By comparing AIC values in the Cox proportional hazards model, the modified three-factor model was the superior prognostic model followed by established ALC/R-IPI, R-IPI, and standard IPI. In conclusion, the addition of the novel factor, ALC, interacts with other established factors in outcome prediction for DLBCL. Development of a new score is needed for a better risk stratification in the rituximab era and would be helpful in the design of future clinical trials. The proposed three-factor model should be validated in large-scale studies.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Rituximab , Taxa de Sobrevida/tendências , Vincristina/administração & dosagem , Adulto JovemRESUMO
Rituximab reforms the treatment of diffuse large B-cell lymphoma (DLBCL) and the prognostic significance of baseline patient features should be reevaluated. Few population-based studies have investigated the association of diabetes mellitus (DM) and outcomes of lymphoma; however, the results remain inconclusive. From January 1, 2000 to December 31, 2009, a total of 468 consecutive newly diagnosed DLBCL patients receiving first-line chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) or rituximab plus CHOP (R-CHOP) were enrolled. Pre-existing DM was defined according to medical history, use of antidiabetic medications, or any record of an abnormal hemoglobin A1c test. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using the Kaplan-Meier method with a log-rank test. CHOP was administered in 194 patients, and 274 patients received R-CHOP. DM was identified in 16.2 % (76/468) of patients. Diabetic patients were older and more performance restricted, compared to the non-DM patients in both the CHOP and R-CHOP groups. In the CHOP group, 5-year PFS and OS were inferior in DM patients (PFS, 32.4 vs. 50.0 % (P = 0.039); OS, 38.2 vs. 62.5 % (P = 0.002)). However, outcomes were similar for both DM and non-DM patients in the context of R-CHOP treatment (PFS, 69.0 vs. 57.3 % (P = 0.179); OS, 76.2 vs. 69.8 % (P = 0.586)). The response rate of chemotherapy in DM patients was also improved to a level similar to non-DM patients with rituximab use. In conclusion, the prognostic significance of preexisting DM in DLBCL patients is changing in the rituximab era. The potentially additional benefit of rituximab in DM patients merits further investigation.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Diabetes Mellitus/mortalidade , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Rituximab , Terapia de Salvação/métodos , Vincristina/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: The objective of this study is to assess the incidence and risk of mood disorders, including major depression, anxiety, and bipolar disorders, in Taiwanese patients after the diagnosis of breast cancer compared with a matched cohort. METHODS: From January 2000 to December 2005, 26,629 newly diagnosed breast cancer patients were enrolled by the Taiwan National Health Insurance program database. The control cohort was selected randomly from 1,000,000 National Health Insurance beneficiaries from a population of 21,400,826 enrolled throughout Taiwan. Each patient was matched with one subject without breast cancer by age, sex, and presence of comorbidities with the same diagnosis index date. The diagnosis of mood disorders was defined by compatible International Classification of Diseases, 9th revision, clinical modification codes plus the prescription of antidepressants for at least 30 days. RESULTS: The overall incidence rate ratio of mood disorders was 1.33 (95% CI 1.28-1.39, p < 0.001) in the breast cancer cohort compared with the matched cohort. The incidence rate ratios for specific mood disorders were 2.06 for bipolar disorder (95% CI 1.37-3.15 p = 0.0003), 1.94 for major depressive disorder (95% CI 1.76-2.13 p < 0.001), and 1.22 for anxiety (95% CI 1.16-1.27 p < 0.001). Independent risk factors for developing mood disorders included breast cancer, as well as age, hypertension, chronic obstructive pulmonary disease, autoimmune disease, ischemic heart disease, and cerebrovascular disease. CONCLUSIONS: Breast cancer is a prominent risk factor for mood disorders, including major depressive disorder, anxiety, and bipolar disorder. The impact is most potent in the first year after diagnosis. Psychological support is a critical issue in these patients.
Assuntos
Transtornos de Ansiedade/epidemiologia , Transtorno Bipolar/epidemiologia , Neoplasias da Mama/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtornos de Ansiedade/psicologia , Doenças Autoimunes/epidemiologia , Transtorno Bipolar/psicologia , Neoplasias da Mama/psicologia , Estudos de Casos e Controles , Transtornos Cerebrovasculares/epidemiologia , Estudos de Coortes , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Hipertensão/epidemiologia , Incidência , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Taiwan/epidemiologia , Adulto JovemRESUMO
In a recent study, Rialdi and colleagues identified a specific vulnerability in ß-catenin mutant hepatocellular carcinoma (HCC) via EZH2-mediated suppression of WNT signaling and revealed the selective anti-HCC activity of WNTinib, a chemical derivative of regorafenib and sorafenib in targeting this vulnerability. Their discoveries highlight the role of EZH2 in modulating WNT signaling and suggest an implication of WNTinihb as a small-molecule inhibitor for the treatment of HCC with activated WNT/ß-catenin.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Wnt , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismoRESUMO
Certain portions of patients with diffuse large B cell lymphoma (DLBCL) do not achieve a complete remission after first-line rituximab combining chemotherapy. This retrospective study aimed to characterize the outcome of patients with DLBCL that achieved partial remission or had stable disease after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). The effects of subsequent treatments and factors associated with event-free survival (EFS) after second-line treatments were analyzed. A total of 103 patients were enrolled and 81 (76.8 %) patients received intensive chemotherapy, whereas the others (23.2 %) received either palliative chemotherapy or supportive care post first-line treatment. Patients receiving intensive chemotherapy had significantly higher EFS (median 7.9 months) than the others; 28 (34.6 %) patients in this group received autologous stem cell transplantation (ASCT), which may have further improved the EFS. An International Prognostic Index (IPI) >2 and absolute lymphocyte count (ALC) at diagnosis <1,000/UL were significant prognostic factors associated with worse EFS. The survival advantage of ASCT remained significant after adjustment for these factors. The results suggest intensive chemotherapy plus ASCT may provide modest disease control in patients with DLBCL who achieve PR or SD to first-line R-CHOP, particularly in those with a higher IPI score and/or low ALC at diagnosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linfoma Difuso de Grandes Células B/fisiopatologia , Linfoma Difuso de Grandes Células B/terapia , Linfopenia/etiologia , Linfopoese/efeitos dos fármacos , Transplante de Células-Tronco de Sangue Periférico , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Hospitais de Veteranos , Humanos , Contagem de Linfócitos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Rituximab , Análise de Sobrevida , Taiwan , Transplante Autólogo , Vincristina/uso terapêuticoRESUMO
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Linfócitos T/metabolismo , Animais , Biomarcadores Tumorais , Linfócitos T CD8-Positivos , Sistemas CRISPR-Cas , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Metionina Adenosiltransferase/sangue , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , S-Adenosilmetionina/metabolismo , TranscriptomaRESUMO
Recent advances in immune checkpoint inhibition, which augment T-cell immune responses, have highlighted the potential of exploiting one's immune system to combat cancer. However, only a relatively small number of non-small cell lung cancer (NSCLC) patients benefit from immune checkpoint blockade due to the immunosuppressive tumor microenvironment. Therefore, combination immunotherapies are now being developed to achieve maximal therapeutic benefits. In this study, we assessed whether a novel erlotinib derivative, TD-92, which possesses anti-tumor effects across several cancer cell lines, could enhance anti-PD-1 treatment. Our results demonstrated that the combined treatment of anti-PD-1 and TD-92 resulted in a potent anti-tumor response in a Lewis lung carcinoma cancer model, as evidenced by the reduced tumor growth and increased survival. Analysis of immune cell population counts revealed that TD-92 reduced the number of pro-tumorigenic CD11b+ F4/80+ tumor-associated macrophages, without significantly affecting the total numbers of other major immunocytes. Further experiments showed that TD-92 induced a marked decline in colony stimulating factor 1 receptor (CSF-1R) expression in macrophage cell lines. The results also suggested that c-Cbl-mediated proteasome degradation was involved in TD-92-mediated CSF-1R downregulation. Our data paves the way for the development of additional combination immunotherapies for NSCLC patients.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismoRESUMO
Accelerated glucose metabolism is critical in hepatocarcinogenesis, but the utilities of different glucose transporter inhibitors in treating hepatocellular carcinoma (HCC) remain largely uncharacterized. In this study, we examined a collection of glucose transporter inhibitors and found differential anti-HCC effects among these compounds. Canagliflozin (CANA), phloretin, and WZB117 decreased cellular glucose influx, but only CANA showed potent growth inhibition in HCC, which indicated a glucose-independent anti-HCC mechanism. Notably, we found that CANA treatment significantly downregulated the expression of ß-catenin in HCC cells in. By co-treating cells with cycloheximide and MG-132, we proved that CANA promoted proteasomal degradation of ß-catenin protein by increasing phosphorylation of ß-catenin, and CANA-induced inactivation of protein phosphatase 2A was identified being responsible for this effect. Moreover, using Huh7 xenografted tumor model, CANA treatment was shown to delay tumor growth and improved the survival of HCC bearing mice. Our study highlights the unique dual ß-catenin-inhibition mechanisms of CANA, which may provide new thoughts on treating HCC patient with concurrent diabetes, and, furthermore, on developing novel treatment targeting metabolic reprogram and/or WNT/ß-catenin signaling in HCC.
Assuntos
Canagliflozina/farmacologia , Proliferação de Células/efeitos dos fármacos , Glucose/metabolismo , beta Catenina/metabolismo , Animais , Canagliflozina/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cicloeximida/farmacologia , Regulação para Baixo/efeitos dos fármacos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transplante Heterólogo , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
AIM: Palbociclib is an oral cyclin-dependent kinase 4/6 inhibitor, which is efficacious in treating breast cancer. Currently, there are numerous active clinical trials testing palbociclib alone or in combination with other medications for treating various types of malignancies. Here, we evaluated the anti-cancer effect of palbociclib in combination with radiation therapy (RT) for treating human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) and addressed the molecular mechanism behind the combination therapy. METHODS: Immunofluorescence staining of γH2AX or 53BP1 was used to determine the effect of palbociclib on double-strand break (DSB) repair. Clonogenic assays, sphere formation and cell death ELISA were performed to study the sensitising effect of palbociclib on radiation-induced cytotoxicity. Signal alteration in DSB repair pathways was examined by Western blot analysis. Finally, we evaluated the in vivo anti-cancer activity and the associated molecular events of the combination therapy in a preclinical HCC xenograft model. RESULTS: Palbociclib affected the kinetics of DNA repair and enhanced the radiation sensitivity of HCC and CCA cells. Importantly, we found that palbociclib inhibits ataxia telangiectasia-mutated (ATM) kinase, the key upstream kinase responding to RT-induced DSBs. Furthermore, we showed that the inhibitory effect of palbociclib on RT-induced ATM kinase activation is mediated by protein phosphatase 5 (PP5). Both in vitro and in vivo investigations revealed that the inhibition of the PP5-ATM axis by palbociclib after DNA damage is responsible for the synergism between palbociclib and RT. CONCLUSION: Our findings provide a novel combination strategy against liver cancer cells. Clinical trials using palbociclib as an adjuvant in RT are warranted.
Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Quimiorradioterapia , Colangiocarcinoma/terapia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/efeitos dos fármacos , Neoplasias Hepáticas/terapia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Histonas/metabolismo , Humanos , Cinética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Tolerância a Radiação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: SET is a multitask oncoprotein that promotes the initiation and progression of cancer. Overexpression of SET has been characterized as being tumor-specific and is associated with adverse clinical outcomes in many different human malignant diseases. Notably, SET has been shown to promote the development of therapeutic resistance in cancer cells. Area covered: In this review, we summarized the currently available evidence relating to the oncogenic roles, biological functions and clinical relevance of SET protein in cancer. The anti-cancer effects of three different SET antagonists undergoing preclinical investigation are also discussed. Expert opinion: Emerging evidence supports the critical role of SET in regulating various different cancer hallmarks. Targeting the SET-associated protein interfaces may be a potential anti-cancer strategy for future development. However, more studies are required to clarify the best strategy to combine SET antagonists with other anti-cancer treatments and to explore possible biomarkers that predict responsiveness.