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1.
Food Sci Nutr ; 8(10): 5673-5682, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33133569

RESUMO

Cruciferous vegetables are primary sources of dietary isothiocyanates (ITCs), a group of phytochemicals showing promising cancer-chemopreventive activities in multiple cancer models. However, no study has thoroughly examined how cooking affects the yields of ITCs from cruciferous vegetables. In this study, a high-performance liquid chromatography (HPLC)-based cyclocondensation assay was performed to examine the ITC yields from four major cruciferous vegetables (broccoli, cabbage, cauliflower, and kale) under six cooking conditions (stir-frying, steaming, microwaving, boiling, stewing, and chip-baking for kale only) and measured the level of ITCs under the raw condition for a comprehensive list of cruciferous vegetables and ITC-containing condiments. A wide range of ITC yields was found across vegetables and condiments. Cooking significantly altered the ITC yields, showing an averagely four-fold increase by lightly cooking (stir-frying, steaming, and microwaving) and a 58% decrease by heavily cooking (boiling, stewing, and chip-baking). These findings will provide the evidence-based cooking guidance on cruciferous vegetable consumption and help better estimate dietary ITC exposure in epidemiologic studies.

2.
Pharmacol Ther ; : 107677, 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32898548

RESUMO

HER2 is a well-known oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in about 20% of breast cancer (BC), which leads to overexpression of HER2 protein, known as HER2-positive BC. Inhibitors of HER2 have significantly improved the prognosis of patients with this subset of BC. Since 1998, seven HER2 inhibitors have been developed to treat this disease. However, drug resistance is common and remains a major unresolved clinical problem. Patients typically show disease progression after some time on treatment. This review discusses the complexity and diversified nature of HER2 signaling, the mechanisms of actions and therapeutic activities of all HER2 inhibitors, the roles of HER2 and other signaling proteins in HER2-positive BC resistant to the inhibitors, the non-cell-autonomous mechanisms of drug resistance, and the heterogeneity of tumor HER2 expression. The review presents the concept that drug resistance in HER2-positive BC results primarily from the inability of HER2 inhibitors to deplete HER2. Emerging therapeutics that are promising for overcoming drug resistance are also discussed.

3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(3): 279-286, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32385990

RESUMO

OBJECTIVE: To discuss the research progress in the field of coronavirus (CoVs) treatment based on the visualization analysis of knowledge graph. METHODS: The related literatures in the field of CoVs treatment were retrieved from the establishment of Web of Science core collection database to February 15th, 2020, and the literature analysis tool of Web of Science database was used to count the annual trend of published literatures. The VOSviewer software was used to analyze the relationship among countries, institutions, authors, clustering and density of subject words. The HistCite software was used to screen important documents and to draw the evolution process of hot spots. The CiteSpace software was used to analyze the breakout points of subject words, so as to find the front and hot spots in this field. RESULTS: A total of 1 747 data were retrieved, with the exception of 17 duplicate data, and 1 730 data were retained for visualization analysis. In terms of literature volume, the literatures on CoVs therapy rose after 2003 and 2012, and the number of published literatures had remained high since 2014. In terms of countries, the main countries that carried out the research on the treatment of CoVs were the United States (n = 613), China (n = 582), Germany (n = 122), Canada (n = 99), etc., and the cooperation among countries was close. In terms of institutions, the number of papers issued by Chinese Academy of Sciences in the field of CoVs treatment ranked first (n = 82), followed by University of Hong Kong of China (n = 74) and Chinese University of Hong Kong of China (n = 58), followed by National Institute of Allergy and Infectious Diseases (n = 37), and the cooperation among various institutions was close. In terms of literature authors, there were two high-yielding authors in the United States [Ralph S. Baric (n = 21) and Kuochen Chou (n = 17)], two Chinese authors [Yuen Kwok-yung (n = 17) and Jiang Shibo (n = 16)] and one Dutch author [Eric J. Snijder (n = 17)]. In terms of the cluster analysis of authors, the authors were closely related in reverse genetics, respiratory infection, receptor binding domain, etc., and the 15 top-cited papers came mainly from China, the United States, Netherlands and other countries, and the literature content represented the frontiers and hot spots in different periods. The treatment hot spots focused on preventing virus adsorption, inhibiting the virus gene nucleic acid replication, transcription and translation. The main subject words were divided into three main categories, namely, CoVs epidemiology, basic research and drug development, in which basic research and drug development were strongly correlated. In the subject words breakthrough analysis, there were time-related breakthrough points in 1991, 1996 and 2002, and the "diagnosis" and "sequence" were continuous hot spots. CONCLUSIONS: Through the visualization analysis of knowledge graph, the development trend and hot spots of CoVs therapy research could be well observed. In this study, the degree of attention in the field of CoVs treatment showed periodic changes, related to the outbreak of new CoVs, and the country, institutions and the author were closely related. The treatment hot spots focused on preventing virus adsorption, inhibiting the virus gene nucleic acid replication, transcription and translation in order to develop new targets of drug.


Assuntos
Infecções por Coronavirus/terapia , Coronavirus , Bibliometria , China , Bases de Dados Factuais , Humanos , Pandemias , Reconhecimento Automatizado de Padrão , Pneumonia Viral , Publicações , Estados Unidos
4.
Cytometry B Clin Cytom ; 98(2): 193-202, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31571381

RESUMO

BACKGROUND: Several studies have used CD157 in white blood cells with or without proaerolysin (fluorescein-labeled proaerolysin [FLAER])-based flow cytometry assays in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We designed a seven-color CD marker panel comprising FLAER, CD15, CD64, CD24, CD14, CD157, and CD45 to verify CD157's clinical applicability and diagnostic performance in a clinical setting. RESULTS: A total of 356 samples were tested. These included 43 PNH-positive samples and 313 PNH-negative samples. PNH clones confirmed by the CD157/FLAER combination were almost identical in size to the clones detected by the CD24/CD14/FLAER combination, and the accuracy of the CD157/FLAER combination was 100% in granulocytes and 99.7% in monocytes. Substitution of FLAER with CD157 resulted in 1.9% and 3.5% false-positives in granulocytes and monocytes, respectively. The accuracy was 98.3% and 96.9% in granulocytes and monocytes, respectively. Moreover, the loss of CD157 expression in granulocytes and monocytes was commonly observed in non-PNH patients. Some monocytes in non-PNH patients had weak expression of CD14 but normal expression of FLAER. In this study, PNH clones in granulocytes were always lower than those in matched monocytes. CONCLUSIONS: We performed the first prospective exploration of the clinical usefulness of FLAER and CD157 in simultaneously recognizing PNH clones in granulocytes and monocytes and verified the applicability of CD157 in substitute for both CD14 and CD24. In the conditions where FLAER is not available, substitution of FLAER with CD157 is acceptable for the identification of PNH clones under the premise of giving full attention to the potential for false-positives.

5.
Int J Lab Hematol ; 41(5): 607-614, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31162830

RESUMO

BACKGROUND: The MRD status detected using multiparameter flow cytometry (MFC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has crucial prognostic value for patients with acute myeloid leukemia (AML) in morphologic complete remission (CR). We designed a novel panel of antibodies to identify aberrant differentiation/maturation profiles of residual leukemia cells in patients who were not diagnosed at our institution, relapsed with an antigenic shift, or lack leukemia-associated immunophenotypes. METHODS: We compared the MRD status detected using MFC and real-time quantitative polymerase chain reaction (RT-qPCR) in the same 158 bone marrow samples collected from 44 AML patients carrying leukemia-specific fusion genes. The clinical performance of the MFC-based MRD status was analyzed in 168 AML patients who exhibited morphologic CR (135) or active disease (33) before HSCT. RESULTS: Strong concordance was found between MFC-based and RT-qPCR-based MRD status (κ = 0.868). Among the patients displaying CR, the positive MRD status detected using MFC was correlated with a worse prognosis [HRs (P values) for relapse, event-free survival, and overall survival: 4.83 (<0.001), 2.23 (0.003), and 1.79 (0.049), respectively]; the prognosis was similar to patients with an active disease before HSCT. Patients with a positive MRD before HSCT might experience a benefit from developing chronic graft-vs-host disease. CONCLUSIONS: The assessment of MRD using our self-built different-from-normal AML-MRD detection panel exhibited reliable sensitivity, specificity, and accuracy. In addition, patients with a positive MRD status before transplantation may have higher risk of relapse and worse survival.


Assuntos
Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Neoplasia Residual/diagnóstico , Doença Aguda , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Citometria de Fluxo/instrumentação , Humanos , Imunofenotipagem/métodos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo , Adulto Jovem
6.
Sci Transl Med ; 11(476)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674653

RESUMO

Resistance to current human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab (Ttzm), is a major unresolved clinical problem in HER2-positive breast cancer (HER2-BC). Because HER2 remains overexpressed in drug-resistant HER2-BC cells, we investigated whether PEPDG278D can overcome the resistance. PEPDG278D is a recombinant enzymatically inactive mutant of human peptidase D, which strongly inhibits HER2 in cancer cells by binding to its extracellular domain. Here, we show that PEPDG278D is highly active in preclinical models of HER2-BC resistant to Ttzm and other HER2 inhibitors and also enhances the therapeutic efficacy of paclitaxel. The therapeutic activity is underscored by its ability to bind to HER2 and free it from protection by mucin 4, disrupt its interplay with other receptor tyrosine kinases, and subsequently direct HER2 for degradation. PEPDG278D also down-regulates epidermal growth factor receptor, which contributes to drug resistance in HER2-BC. In contrast, Ttzm, whose therapeutic activity also depends on its binding to the extracellular domain of HER2, cannot perform any of these functions of PEPDG278D PEPDG278D inhibits HER2-BC cells and tumors that carry clinically relevant molecular changes that confer resistance to Ttzm. Our results show that HER2 remains a critical target in drug-resistant HER2-BC and that PEPDG278D is a promising agent for overcoming drug resistance in this disease.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptor ErbB-2/metabolismo , Proteínas Recombinantes/uso terapêutico , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Endocitose , Feminino , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos Nus , Camundongos SCID , Mucina-4/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Multimerização Proteica , Proteínas Recombinantes/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento
7.
Cancer Causes Control ; 30(2): 187-193, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656539

RESUMO

PURPOSE: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors. METHODS: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies. RESULTS: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection. CONCLUSIONS: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.


Assuntos
Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Sobreviventes de Câncer , Dieta , Progressão da Doença , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Neoplasias da Bexiga Urinária/genética
8.
Cancer Med ; 7(11): 5604-5610, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30306738

RESUMO

Bladder cancer risk is 3-4 times higher in men than women, but the reason is poorly understood. In mice, male bladder is also more susceptible than female bladder to 4-aminobiphenyl (ABP), a major human bladder carcinogen; however, female liver is more susceptible than male liver to ABP. We investigated the role of sulfotransferase (Sult) in gender-related bladder and liver susceptibility to ABP. Sulfation reactions of aromatic amine bladder carcinogens catalyzed by Sult may generate highly unstable and toxic metabolites. Therefore, liver Sult may decrease bladder exposure to carcinogens by promoting their toxic reactions in the liver. Notably, the expression of several liver Sults is suppressed by androgen in male mice. Here, we show that two Sults are critical for gender-related bladder susceptibility to ABP in mice. We measured tissue level of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP), a principal ABP-DNA adduct, as readout of tissue susceptibility to ABP. We identified Sutl1a1 and to a lesser extent Sult1d1 as Sults that promote dG-C8-ABP formation in hepatic cells. In mice, gender gap in bladder susceptibility to ABP was narrowed by knocking out Sult1a1 and was almost totally eliminated by knocking out both Sutl1a1 and Sult1d1. This was accompanied by dramatic decrease in ABP genotoxicity in the liver (>97%). These results show the strong impact of the Sults on bladder and liver susceptibility to a human carcinogen. Because liver expression of both Sult1a1 and Sutl1d1 is suppressed by androgen in male mice, our results suggest that androgen renders bladder more exposed to ABP in male mice by suppressing Sult-mediated ABP metabolism in liver, which increases bladder delivery of carcinogenic metabolites.


Assuntos
Compostos de Aminobifenil/efeitos adversos , Compostos de Aminobifenil/análise , Desoxiguanosina/análogos & derivados , Fígado/química , Sulfotransferases/metabolismo , Bexiga Urinária/efeitos dos fármacos , Androgênios/metabolismo , Animais , Arilsulfotransferase/genética , Arilsulfotransferase/metabolismo , Linhagem Celular , Desoxiguanosina/análise , Feminino , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Caracteres Sexuais , Sulfotransferases/genética , Bexiga Urinária/química
9.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1087-1088: 49-60, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29709872

RESUMO

4-Aminobiphenyl (4-ABP) which is primarily formed during tobacco combustion and overheated meat is a major carcinogen responsible for various cancers. Its adducted form, N-deoxyguanosine-C8-4-aminobiphenyl (dG-C8-4-ABP), has long been employed as a biomarker for assessment of the risk for cancer. In this review, the metabolism and carcinogenisity of 4-ABP will be discussed, followed by a discussion of the current common approaches of analyzing dG-C8-4-ABP. The major part of this review will be on the history and recent development of key methods for detection and quantitation of dG-C8-4-ABP in complex biological samples and their biological applications, from the traditional 2P-postlabelling and immunoassay methods to modern liquid chromatography-mass spectrometry (LC-MS) with the latter as the focus. Many vital biological discoveries based on dG-C8-4-ABP have been published by using the nanoLC-MS with column switching platform in our laboratory, which has also been adopted and further improved by many other researchers. We hope this review can provide a perspective of the challenges that had to be addressed in reaching our present goals and possibly bring new ideas for those who are still working on the frontline of DNA adducts area.


Assuntos
Compostos de Aminobifenil/análise , Biomarcadores/análise , Cromatografia Líquida/métodos , Desoxiguanosina/análogos & derivados , Espectrometria de Massas/métodos , Compostos de Aminobifenil/farmacocinética , Animais , Desoxiguanosina/análise , Desoxiguanosina/farmacocinética , Humanos , Limite de Detecção , Modelos Lineares , Camundongos , Técnicas Analíticas Microfluídicas , Exposição Ocupacional , Distribuição Tecidual
10.
Oncotarget ; 9(5): 5614-5626, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464022

RESUMO

We recently discovered a plasma proteolysis pathway, termed the FXII-FVII pathway which is composed of coagulation proteases, and found it to be mainly responsible for the clearance of Aß42 in the plasma in mice. Aß42 and Aß40 are the main Aß forms in Alzheimer's disease (AD). In the present study, in vitro assays, wild type (WT) mice and J20 mice (a transgenic AD model) are used to assess the degradation of Aß40 and Aß42 by the FXII-FVII pathway and the impact of anticoagulants on such degradation. Four clinically available and mechanistically distinct anticoagulants are evaluated, including dabigatran, enoxaparin (EP), rivaroxaban and warfarin. Each anticoagulant significantly elevates plasma level of synthetic Aß42 in WT mice, among which EP is the most effective. The differential efficacies of the anticoagulants in elevating plasma Aß42 level match closely with their inhibitory mechanisms towards the FXII-FVII pathway. Plasma Aß40 is also degraded by the FXII-FVII pathway and is protected by EP. Moreover, the FXII-FVII pathway is significantly activated in J20 mice, but EP inhibits the activation and significantly elevates plasma levels of both Aß40 and Aß42. Taken together, our results shed new light on Aß metabolism, reveal a novel function of anticoagulants, and suggest a novel approach to potentially developing plasma Aß as an AD biomarker.

11.
Nat Commun ; 8(1): 2052, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29233996

RESUMO

p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases.


Assuntos
Apoptose/fisiologia , Dipeptidases/fisiologia , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citoplasma/metabolismo , Dipeptidases/genética , Doxorrubicina/farmacologia , Ensaios Enzimáticos , Técnicas de Silenciamento de Genes , Humanos , Peróxido de Hidrogênio/farmacologia , Mitocôndrias/metabolismo , Mutagênese Sítio-Dirigida , Fosforilação , Ligação Proteica/fisiologia , Domínios Proteicos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Estresse Fisiológico/efeitos da radiação , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Oncotarget ; 7(27): 40919-40938, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27248165

RESUMO

Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid ß1-42 (Aß1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes. Therefore, FXII and FVIIa serve as the sensor/initiator and executioner, respectively, for the proteolysis pathway. Moreover, activation of this pathway by one probe leads to the degradation of all three probes. Significant activation of this pathway follows tissue injury and may also occur in other disorders, e.g., Alzheimer's disease, of which Aß1-42 is a key driver. However, enoxaparin, a clinically used anticoagulant, inhibits the proteolysis pathway and elevates plasma levels of the probes. Enoxaparin may also mitigate potential impact of activators of the proteolysis pathway on coagulation. Our results suggest that the proteolysis pathway is important for maintaining low levels of various plasma proteins. Our finding that enoxaparin inhibits this pathway provides a means to control it. Inhibition of this pathway may facilitate the development of disease biomarkers and protein therapeutics, e.g., plasma Aß1-42 as a biomarker of Alzheimer's disease or recombinant human prolidase as an antitumor agent.


Assuntos
Coagulação Sanguínea , Hemostasia/fisiologia , Peptídeo Hidrolases/sangue , Proteólise , Peptídeos beta-Amiloides/sangue , Animais , Coagulação Sanguínea/genética , Fator VII/genética , Fator VII/metabolismo , Fator XII/genética , Fator XII/metabolismo , Hemostasia/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/sangue , Transdução de Sinais/genética
13.
Oncotarget ; 7(27): 42340-42352, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27286447

RESUMO

ErbB1 and ErbB2 are oncogenic cell surface receptor tyrosine kinases, linked to many forms of human cancer, and are major cancer therapeutic targets. Many lines of evidence indicate that targeting ErbB1 and ErbB2 is an important cancer therapeutic approach. We recently found that a recombinant enzymatically-inactive mutant of human prolidase, i.e., hPEPD-G278D, is an inhibitory ligand of ErbB2 and strongly inhibits ErbB2-overexpressing cells in vitro and in vivo. hPEPD-G278D also binds to ErbB1. Here, we show that hPEPD-G278D binds to ErbB1 with high affinity, initially activating ErbB1 but later silencing it, and that deletion of subdomain 2 in ErbB1 extracellular domain abolishes the binding. The proliferation of ErbB1-overexpressing cells is strongly inhibited by hPEPD-G278D, regardless of ErbB2 expression or cell type, whereas cells lacking ErbB1 and ErbB2 are insensitive to it. In contrast, EGF, another ErbB1 ligand, either stimulates or mildly inhibits cell proliferation. Moreover, hPEPD-G278D treatment of mice bearing ErbB1-overexpressing tumors leads to tumor regression, which is accompanied by down regulation and decreased phosphorylation of ErbB1 and ErbB2 as well as decreased phosphorylation of downstream signaling molecules and activation of apoptosis in the tumor tissues. We conclude that hPEPD-G278D is a dual inhibitor of ErbB1 and ErbB2 and selectively targets cancer cells overexpressing ErbB1 and/or ErbB2. Moreover, our finding that both receptors are silenced in cancer cells by hPEPD-G278D highlights an unusual consequence of ligand-receptor interaction.


Assuntos
Dipeptidases/metabolismo , Receptores ErbB/antagonistas & inibidores , Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Ligantes , Camundongos , Proteínas Mutantes/metabolismo , Fosforilação , Ligação Proteica , Proteínas Recombinantes/metabolismo , Indução de Remissão , Transdução de Sinais/efeitos dos fármacos
14.
Am J Cancer Res ; 5(8): 2516-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26396928

RESUMO

Although in vitro studies have shown that isothiocyanates (ITCs) can synergistically sensitize cancer cells to cisplatin treatment, the underlying mechanisms have not been well defined, and there are no in vivo demonstrations of this synergy. Here, we report the in vitro and in vivo data for the combination of allyl isothiocyanate (AITC), one of the most common naturally occurring ITCs, with cisplatin. Our study revealed that cisplatin and AITC combination synergistically inhibits cancer cell growth and colony formation, and enhances apoptosis in association with the downregulation of antiapoptotic proteins Bcl-2 and survivin. Importantly, the in vivo combination treatment suppresses human tumor growth in animal models without observable increases in toxicity (body weight loss) in comparison with single agent treatment. Furthermore, our data revealed that addition of AITC to cisplatin treatment changes the profile of G2/M arrest (e.g. increase in M phase cell number) and significantly extends the duration of G2/M arrest in comparison with cisplatin treatment alone. To explore the underlying mechanism, we found that AITC treatment rapidly depletes b-tubulin. Combination of AITC and cisplatin inhibits the expression of G2/M checkpoint-relevant proteins including CDC2, cyclin B1 and CDC25. Together, our findings reveal a novel mechanism for AITC enhancing cisplatin efficacy and provides the first in vivo evidence to support ITCs as potential candidates for developing new regimens to overcome platinum resistance.

15.
Curr Pharmacol Rep ; 1(4): 272-282, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26273545

RESUMO

Approximately 80% of human bladder cancers (BC) are non-muscle invasive when first diagnosed and are usually treated by transurethral tumor resection. But 50-80% of patients experience cancer recurrence. Agents for prevention of primary BC have yet to be identified. Existing prophylactics against BC recurrence, e.g., Bacillus Calmette-Guerin (BCG), have limited efficacy and utility; they engender significant side effects and require urethral catheterization. Many cruciferous vegetables, rich sources of isothiocyanates (ITCs), are commonly consumed by humans. Many ITCs possess promising chemopreventive activities against BC and its recurrence. Moreover, orally ingested ITCs are selectively delivered to bladder via urinary excretion. This review is focused on urinary delivery of ITCs to the bladder, their cellular uptake, their chemopreventive activities in preclinical and epidemiological studies that are particularly relevant to prevention of BC recurrence and progression, and their chemopreventive mechanisms in BC cells and tissues.

16.
EBioMedicine ; 2(5): 396-405, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26086037

RESUMO

ERBB2 is an oncogenic receptor tyrosine kinase overexpressed in a subset of human breast cancer and other cancers. We recently found that human prolidase (PEPD), a dipeptidase, is a high affinity ERBB2 ligand and cross-links two ERBB2 monomers. Here, we show that recombinant human PEPD (rhPEPD) strongly inhibits ERBB2-overexpressing tumors in mice, whereas it does not impact tumors without ERBB2 overexpression. rhPEPD causes ERBB2 depletion, disrupts oncogenic signaling orchestrated by ERBB2 homodimers and heterodimers, and induces apoptosis. The impact of enzymatically-inactive mutant rhPEPDG278D on ERBB2 is indistinguishable from that of rhPEPD, but rhPEPDG278D is superior to rhPEPD for tumor inhibition. The enzymatic function of rhPEPD stimulates HIF-1α and other pro-survival factors in tumors, which likely attenuates its antitumor activity. rhPEPDG278D is also attractive in that it may not interfere with the physiologic function of endogenous PEPD in normal cells. Collectively, we have identified a human protein as an inhibitory ERBB2 ligand that inhibits ERBB2-overexpressing tumors in vivo. Several anti-ERBB2 agents are on the market but are hampered by drug resistance and high drug cost. rhPEPDG278D may synergize with these agents and may also be highly cost-effective, since it targets ERBB2 with a different mechanism and can be produced in bacteria.

17.
Oncotarget ; 6(2): 836-45, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25596734

RESUMO

Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator.


Assuntos
Compostos de Aminobifenil/toxicidade , Dano ao DNA , Fígado/efeitos dos fármacos , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/efeitos dos fármacos , Animais , Feminino , Humanos , Masculino , Camundongos
18.
Mol Cell ; 53(6): 916-928, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24613345

RESUMO

Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.


Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fibrose Pulmonar/genética , Animais , Sítios de Ligação , Bleomicina , Linhagem Celular Tumoral , Genes Reporter , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Luciferases/genética , Luciferases/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Células NIH 3T3 , Regiões Promotoras Genéticas , Ligação Proteica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio , Transdução de Sinais
19.
Artigo em Inglês | MEDLINE | ID: mdl-24171436

RESUMO

It has long been known that bladder cancer (BC) incidence is approximately four-fold higher in men than in women in the United States, and a similar disparity also exists in other countries. The reason for this phenomenon is not known, which impedes progress in BC prevention. However, BC incidence is also significantly higher in male animals than in their female counterparts after treatment with aromatic amines, which are principal human bladder carcinogens. These animal studies and related studies in the context of available human data provide significant insight into what may drive the excessive BC risk in men, which is the focus of this article. The carcinogenicity and biotransformation of bladder carcinogens as well as the impact of sex hormones on these processes are discussed, highlighting the novel concept that the gender disparity in BC risk may result primarily from the interplay of androgen, estrogen, and liver, with the liver functioning via its metabolic enzymes as the main decider of bladder exposure to carcinogens in the urine and the male and female hormones exerting opposing effects on carcinogenesis in the bladder and likely also on liver enzymes handling bladder carcinogens. The findings may facilitate further investigation into the mechanism of gender disparity in BC risk and may also have important implications for BC prevention.


Assuntos
Carcinógenos Ambientais/toxicidade , Hormônios Esteroides Gonadais/metabolismo , Fígado/efeitos dos fármacos , Neoplasias da Bexiga Urinária/epidemiologia , Animais , Biotransformação , Carcinógenos Ambientais/farmacocinética , Feminino , Humanos , Fígado/metabolismo , Masculino , Camundongos , Ratos , Fatores de Risco , Fatores Sexuais , Neoplasias da Bexiga Urinária/induzido quimicamente
20.
Carcinogenesis ; 34(11): 2593-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23946495

RESUMO

Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1 mg/kg and celecoxib at 10 mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Isotiocianatos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Western Blotting , Caspases/metabolismo , Celecoxib , Células Cultivadas , Dinoprostona/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Conservantes de Alimentos/farmacologia , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Invasividade Neoplásica , Ratos , Ratos Endogâmicos F344 , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
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