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1.
Anticancer Res ; 40(1): 221-227, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892570

RESUMO

BACKGROUND/AIM: Autophagy can be either tumor promotive or suppressive. We previously identified an autophagy-inducing activity in the 30-100 kDa fraction of areca-nut-extract (ANE 30-100K) and showed that several tumor cells subjected to chronic ANE 30-100K stimulation (CAS) exhibited higher resistance against stressed environments including serum-free (SF) conditions in vitro. Herein, we aimed to assess whether CAS can also provide growth advantages for tumor cells in vivo and the therapeutic effect of autophagy inhibition on CAS-treated tumors. MATERIALS AND METHODS: Esophageal CE81T/VGH cells and nude mice were used as experimental models. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), as well as another anticancer drug cisplatin (DDP), were chosen to challenge CAS-treated CE81T/VGH cells in vitro and in vivo. RESULTS: CAS-treated CE81T/VGH cells expressed higher levels of microtubule-associated protein 1 light chain 3A/B-II (LC3-II) and beclin 1 proteins, and showed stronger resistance to SF and hypoxia conditions, that were mitigated by CQ or 3-MA in vitro. Furthermore, CAS-treated CE81T/VGH cells induced significantly larger tumors in mice, which were also attenuated by single 3-MA or CQ treatment. Finally, the combined treatment of 3-MA or CQ with DDP further up-regulated DDP-induced caspase-3 activity in vitro and exhibited synergistic anti-tumor effects on mice. CONCLUSION: CAS may up-regulate tumoral autophagy and provide growth advantage for tumors both in vitro and in vivo. Furthermore, autophagy inhibition alone or in combination with DDP may achieve positive therapy for tumors encountered with CAS.


Assuntos
Areca/química , Autofagia , Neoplasias/patologia , Nozes/química , Regulação para Cima , Animais , Autofagia/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus
2.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892559

RESUMO

BACKGROUND/AIM: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically. MATERIALS AND METHODS: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients. Protein expressions were analyzed after drug treatment. RESULTS: Taxotere inhibited tumor growth of NSCLC cells harboring drug resistance, and reduced the expression of phosphorylated MET proto-oncogene, receptor tyrosine kinase (MET). A tumor-inhibitory effect of taxotere was also demonstrated in vivo in xenografts in mice, patient-derived primary lung tumor cells and patient-derived xenograft with concomitant repression of phosphorylated MET expression. Chemotherapeutic and MET-targeting drug exhibited a synergistic cell growth-inhibitory effect. CONCLUSION: These results suggest that the anticancer drug taxane may be an adjuvant for lung tumors exhibiting enhanced signaling of MET networks.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31296605

RESUMO

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/genética , Melanoma/secundário , Neoplasias/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fluxo de Trabalho
4.
Recent Results Cancer Res ; 215: 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605224

RESUMO

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.


Assuntos
Separação Celular/métodos , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes , RNA Neoplásico/análise , Progressão da Doença , Humanos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , RNA Neoplásico/genética
5.
J Enzyme Inhib Med Chem ; 35(1): 265-279, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31790602

RESUMO

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade
6.
Cell Physiol Biochem ; 53(S1): 52-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31854954

RESUMO

Kv1.3 is a voltage gated potassium channel located in the plasma membrane, as well as at intracellular levels, such as mitochondria (mitoKv1.3), nucleus and Golgi apparatus. The plasma membrane channel has been shown to be important for cell proliferation, while the mitochondrial counterpart has been related to modulation of cell death. Moreover, altered expression of Kv1.3 was observed in various tumors and Kv1.3 seems to be involved in development and progression of various cancerous forms. Recent experimental evidences have proved that pharmacological inhibition of the mitoKv1.3 succeeded in reducing up to 90% of tumor volume in vivo in orthotopic mouse model. Furthermore, mitoKv1.3 modulation could impact on cell proliferation as well as on regulation of intracellular signaling pathways. Indeed, the treatment with sub-lethal doses of mitoKv1.3 inhibitors can downregulate Wnt-ß catenin signaling by reducing mitochondrial ATP production and triggering ER-stress. In this review, we describe the role of the mitoKv1.3 in cell death, cancer and intracellular signaling. We will discuss how pharmacological modulation of mitochondrial potassium fluxes impact on mitochondrial membrane potential, reactive oxygen species production and ATP synthesis. All these changes in mitochondrial fitness are related to cell proliferation as well as to cell death and finally on cancer development and progression, so Kv1.3 (and mitoKv1.3) could be now considered a new oncological target.


Assuntos
Canal de Potássio Kv1.3/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Animais , Apoptose , Proliferação de Células , Estresse do Retículo Endoplasmático , Canal de Potássio Kv1.3/antagonistas & inibidores , Canal de Potássio Kv1.3/genética , Neoplasias/patologia , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
7.
Cell Physiol Biochem ; 53(S1): 63-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860207

RESUMO

Mitochondria play a central role in cancer development, by contributing to most of the classical hallmarks of cancer, including sustained proliferation, metabolic re-programming, apoptosis resistance, invasion and induction of angiogenesis [1]. In addition, mitochondria affect also the function of anti- and pro-tumoral immune cells in the tumor microenvironment. Mitochondria harbor a plethora of regulated ion channels whose function is related to ion/ metabolite transport and to fine-tuning of mitochondrial membrane potential as well as of reactive oxygen species release. As a consequence, growing evidence link ion channels located both in the outer and inner mitochondrial membranes to several cancer hallmarks. The present review summarizes our recent knowledge about the participation and role of mitochondrial channels leading to acquisition of cancer hallmarks and thus to cancer progression.


Assuntos
Canais Iônicos/metabolismo , Mitocôndrias/patologia , Neoplasias/patologia , Animais , Apoptose , Proliferação de Células , Progressão da Doença , Humanos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
8.
J Photochem Photobiol B ; 201: 111648, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710924

RESUMO

Superparamagnetic iron oxide nanoparticles (SPIONs) have been recently recognized as highly efficient photothermal therapy (PTT) agents. Here, we demonstrate, for the first time to our knowledge, dose and laser intensity dependent PTT potential of small, spherical, 3-aminopropyltrimethoxysilane coated cationic superparamagnetic iron oxide nanoparticles (APTMS@SPIONs) in aqueous solutions upon irradiation at 795 nm. Indocyanine green (ICG) which has been recently used for photodynamic therapy (PDT), was loaded to APTMS@SPIONs to improve the stability of ICG and to achieve an effective mild PTT and PDT (dual therapy) combination for synergistic therapeutic effect on cancer cells via a single laser treatment in the near infrared (NIR). Neither APTMS@SPIONs nor ICG-APTMS@SPIONs showed dark toxicity on MCF7 breast and HT29 colon cancer cell lines. A safe laser procedure was determined as 10 min irradiation at 795 nm with 1.8 W/cm2 of laser intensity, at which APTMS@SPION did not cause a significant cell death. However, free ICG reduced cell viability at and above 10 µg/ml under these conditions along with generation of reactive oxygen species (ROS), more effectively in MCF7. ICG-APTMS@SPION treated cells showed 2-fold increase in ROS generation and near complete cell death at and below 5 µg/ml ICG dose, even in less sensitive HT29 cells after a single laser treatment at NIR, which would be safe for the healthy tissue and provide a longer penetration depth. Besides, both components can be utilized for diagnosis and the overall composition may be used for optical-image guided phototherapy in the NIR region.


Assuntos
Verde de Indocianina/química , Nanopartículas de Magnetita/toxicidade , Propilaminas/química , Silanos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Verde de Indocianina/farmacologia , Raios Infravermelhos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/terapia , Fotoquimioterapia , Fototerapia , Espécies Reativas de Oxigênio/metabolismo , Temperatura Ambiente
9.
Biochemistry (Mosc) ; 84(11): 1233-1246, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760914

RESUMO

Cellular redox homeostasis involves a combination of redox processes and corresponding regulatory systems and represents an important factor ensuring cell viability. Redox-dependent regulation of cellular processes is a multi-level system including not only proteins and enzyme complexes, but also non-coding RNAs, among which an important role belongs to microRNAs. The review focuses on the involvement of miRNAs in the redox-dependent regulation of both ROS (reactive oxygen species)-generating enzymes and antioxidant enzymes with special emphasis on the effects of miRNAs on redox-dependent processes in tumor cells. The impact of ROS on the miRNA expression and the role of the ROS/miRNA feedback regulation in the cell redox state are discussed.


Assuntos
MicroRNAs/metabolismo , Animais , Humanos , MicroRNAs/química , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução , Estresse Oxidativo , Oxirredutases/metabolismo , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo
10.
Biochemistry (Mosc) ; 84(9): 1028-1039, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693462

RESUMO

Here, we put forward the hypothesis on the mechanism of functioning of cancer stem cells, provided that they exist. The hypothesis is based on the following postulates. 1) Paracrine exchange between cancer and stromal cells is efficient only if they are in a close contact and form a synapse-like cleft between them for the cell-cell crosstalk. The concentration of paracrine signaling molecules in the cleft is high because of the cleft small volume. 2) Cancer stem cells per se do not exist. Instead, there are cancer stem complexes formed by cancer cells tightly bound to stromal cells (portable niches) that exchange paracrine signals. 3) Cancer stem complex is a complex system with newly emerged properties, such as a stemness and resistance to external impacts, including therapeutic interventions. 4) The stemness manifests itself as the ability of cancer cells within the complex to divide asymmetrically: one daughter cell remains in the complex forming a renewed stem complex, whereas the other daughter cell detaches from the complex and transforms in a non-stem cell capable of differentiation. 5) An increased resistance of a cancer stem complex is due to the integration of its intrinsic defense systems through the exchange of paracrine signals, i.e., represents a microresistance at the cell level. 6) Cancer stem complexes can stochastically dissociate with the formation of non-stem cancer cells. Partially differentiated non-stem cancer cells are able to stochastically bind to the stromal component, dedifferentiate under the action of paracrine signals, and form new cancer stem complexes. Therefore, a tumor is a flexible system existing in the pseudo-equilibrium state. Such systems comply with the Le Chatelier's principle stating that an equilibrium system under the action of external factors activates the processes antagonistic to the changes (homeostasis). This promotes tumor resistance at the level of cell populations, i.e., the macroresistance. 7) The portable niche travels with the cancer cell during metastasis. We propose a general therapeutic strategy targeting the contacts between cancer and stromal cells. The disruption of these contacts should lead to the destruction of cancer stem complexes and elimination of tumors.


Assuntos
Neoplasias/genética , Neoplasias/patologia , Nicho de Células-Tronco/fisiologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
11.
Biochemistry (Mosc) ; 84(9): 1047-1056, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693464

RESUMO

Plant hormones produce cytotoxic effect on human cells and can trigger the processes unrelated to cell death, e.g., biosynthetic system stress. The goal of this study was to investigate activation of the endoplasmic reticulum (ER) stress by jasmonic acid (JA) and to distinguish between the responses of cultured immortalized non-tumorigenic HaCaT cells and epidermoid carcinoma A431 cells to this plant hormone. JA was used in the concentration of 2 mM, as it suppressed cell proliferation in both cell lines. We analyzed expression of genes associated with the activation of ER stress (GRP78, ATF4, CHOP), the structure of the ER and Golgi complex, and synthetic processes in the HaCaT and A431 cell lines. JA induced expression of genes responsible for the activation of ER stress and caused hypertrophic changes in the Golgi complex in both cell lines. However, the patterns of gene expression in the HaCaT and A431 cells were different, and higher levels of involucrin synthesis were observed in A431 but not in HaCaT cells, suggesting that JA activated differentiation of the tumor A431 cells only. Therefore, JA induced ER stress in both cell lines, but the consequences of ER stress were different for the epidermal immortalized non-tumorigenic and tumor cells.


Assuntos
Ciclopentanos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/patologia , Neoplasias/patologia , Oxilipinas/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epidérmicas/citologia , Humanos , Neoplasias/metabolismo , Relação Estrutura-Atividade
12.
Biochemistry (Mosc) ; 84(10): 1129-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694509

RESUMO

Metabolic reprogramming is one of the central features of transformed cells. Elucidation of interactions between oncogenic signaling and cell metabolic processes has become the basis for extensive studies of metabolism reprogramming in tumor tissue. The review summarizes the key results of studies on the catabolic and anabolic rearrangements in tumor cells with special emphasis on carbohydrate, lipid, amino acid, and acetate metabolism determining the cancer phenotype of cells.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Humanos , Fenótipo
14.
Enzymes ; 46: 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727271

RESUMO

Chick chorioallantoic membrane (CAM) assay provides a convenient and versatile model for the study of tumor formation, angiogenesis and metastasis. While the assay has been used for more than 100 years, the CAM assay has recently received renewed interest. One of the recent interests comes from the development of Precision Medicine in cancer therapy. The idea is to develop treatments that are tailor-made for each individual patient. For this to happen, patient-derived tumor models are critical and the CAM assay can make significant contribution. The other development concerns various applications of the CAM assay. Using this assay, various reagents have been identified. This includes sensitizers for radiation therapy and photodynamic therapy. We also discuss boron neutron capture therapy (BNCT) that is based on the splitting of boron-10 upon exposure to neutron beam. Recently, various boron-10 reagents have been developed and they can be examined for their efficacy for BNCT therapy using the CAM assay.


Assuntos
Terapia por Captura de Nêutron de Boro , Membrana Corioalantoide/patologia , Neoplasias/patologia , Animais , Embrião de Galinha , Modelos Animais de Doenças , Humanos
15.
Enzymes ; 46: 11-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727272

RESUMO

In vivo experimental models are still essential for advancing our understanding of cancer and developing novel therapeutic strategies, despite rapid and remarkable developments in cellular and molecular technologies. Multiple patient-derived tumor xenograft (PDX) models, in which primary cancer tissues or cells are transplanted into immunodeficient mice, have been developed. PDX models are widely used in the field of precision cancer medicine. The purpose of this chapter is to introduce the chick embryo xenograft model, which has a longer history than the athymic nude mouse model.


Assuntos
Transplante de Neoplasias , Neoplasias/patologia , Animais , Embrião de Galinha , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Transplante Heterólogo
16.
Enzymes ; 46: 37-57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727276

RESUMO

Many types of in vivo animal tumor models have been established. Among these, the chicken chorioallantoic membrane (CAM) model has proven to be particularly useful for transplanting various types of cancer cell lines or tumor tissues to study tumor formation, angiogenesis and metastasis. The CAM model is useful as an animal tumor model, as tumor could be rapidly formed. The tumor formation occurs in 3-4 days, much faster than in mouse models. In addition, the CAM model can be used for drug screening for cancer therapy. This chapter provides an overview of various types of CAM tumor models.


Assuntos
Membrana Corioalantoide/patologia , Neoplasias/patologia , Animais , Embrião de Galinha , Modelos Animais de Doenças , Camundongos , Neovascularização Patológica
17.
Life Sci ; 237: 116952, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622608

RESUMO

Cancer stem cells (CSC) constitute a small area of the tumor mass and are characterized by self-renewal, differentiation and the ability to promote the development of secondary chemo-resistant tumors. Self-renewal of CSCs is regulated through various signaling pathways including Hedgehog, Notch, and Wnt/ß-catenin pathways. A few surface markers have been identified, which provide a means of targeting CSCs according to tumor type. Depending on the proximity of CSCs to the tumor hypoxic niche, hypoxia-inducible factors (HIFs) can play a critical role in modulating several CSC-related characteristics. For instance, the upregulation of HIF-1 and HIF-2 at tumor sites, which correlates with the expansion of CSCs and poor cancer prognosis, has been demonstrated. In this review, we will discuss the mechanisms by which hypoxia enhances the development of CSCs in the tumor microenvironment. Targeting HIFs in combination with other common therapeutics is pre-requisite for effective eradication of CSCs.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Hipóxia/fisiopatologia , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
18.
Cell Biochem Biophys ; 77(4): 293-308, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31598831

RESUMO

Appropriate mechanical forces on cells are vital for normal cell behaviour and this review discusses the possibility that tumour initiation depends partly on the disruption of the normal physical architecture of the extracellular matrix (ECM) around a cell. The alterations that occur thence promote oncogene expression. Some questions, that are not answered with certainty by current consensus mechanisms of tumourigenesis, are elegantly explained by the triggering of tumours being a property of the physical characteristics of the ECM, which is operative following loading of the tumour initiation process with a relevant gene variant. Clinical observations are consistent with this alternative hypothesis which is derived from studies that have, together, accumulated an extensive variety of data incorporating biochemical, genetic and clinical findings. Thus, this review provides support for the view that the ECM may have an executive function in induction of a tumour. Overall, reported observations suggest that either restoring an ECM associated with homeostasis or targeting the related signal transduction mechanisms may possibly be utilised to modify or control the early progression of cancers. The review provides a coherent template for discussing the notion, in the context of contemporary knowledge, that tumourigenesis is an alliance of biochemistry, genetics and biophysics, in which the physical architecture of the ECM may be a fundamental component. For more definitive clarification of the concept there needs to be a phalanx of experiments conceived around direct questions that are raised by this paper.


Assuntos
Carcinogênese/metabolismo , Neoplasias/patologia , Envelhecimento , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Mutação , Neoplasias/metabolismo , Transdução de Sinais , Estresse Mecânico
19.
BMC Infect Dis ; 19(1): 836, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601195

RESUMO

BACKGROUND: Moraxella nonliquefaciens is a usually non-pathogenic biofilm-producing Gram-negative coccobacillus which may colonize the upper respiratory tract, rarely causing invasive disease. Although very rare, bloodstream infections caused by this organism have been described, showing often a fatal outcome. Here, we report the case of a pediatric cancer patient with bloodstream infection and sepsis due to M. nonliquefaciens showing full recovery after appropriate antibiotic treatment. CASE PRESENTATION: A three-year-old boy with stage IV neuroblastoma was admitted for high-dose chemotherapy with autologous stem cell rescue after standard neuroblastoma treatment. Despite receiving antimicrobial prophylaxis with trimethoprim/sulfamethoxazole, acyclovir and amphothericin B, the patient presented with fever of up to 39.5 °C and neutropenia. Besides a chemotherapy-related mucositis and an indwelling Broviac catheter (removed), no infection focus was identified on physical examination. Moraxella nonliquafaciens was identified in blood cultures. After antibiotic treatment and neutrophil recovery, the patient was fit for discharge. CONCLUSIONS: The case described highlights the importance of an otherwise non-pathogenic microorganism, especially in immunosupressed cancer patients. It should be kept in mind that, although very infrequently, Moraxella nonliquefaciens may cause bloodstream infections that can be successfully treated with prompt focus identification and antibiotic therapy.


Assuntos
Bacteriemia/diagnóstico , Moraxella/isolamento & purificação , Neoplasias/patologia , Sepse/diagnóstico , Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Bacteriemia/complicações , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Pré-Escolar , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neutropenia/diagnóstico , Neutropenia/etiologia , Sepse/etiologia , Sepse/microbiologia
20.
Chem Commun (Camb) ; 55(86): 12956-12959, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31602444

RESUMO

A bimetallic complex, containing Mn(ii) and Cu(ii) moieties, was synthesized for chemodynamic therapy (CDT) of cancer. The complex was capable of generating a hydroxyl radical (˙OH) via a Fenton-like reaction involving a Mn complex, and simultaneously depleting glutathione via a Cu complex induced oxidative reaction, thereby enhancing the efficiency of CDT.


Assuntos
Complexos de Coordenação/química , Cobre/química , Glutationa/metabolismo , Manganês/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Glutationa/química , Humanos , Radical Hidroxila/metabolismo , Azul de Metileno/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia
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