RESUMO
Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Ácidos Oleicos/farmacologia , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Glioma/metabolismo , Glioma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Lipídeos de Membrana/química , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Nus , Microscopia Confocal , Ácidos Oleicos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Temozolomida , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismoRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. METHODS: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated variables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. RESULTS: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. CONCLUSION: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread.
Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/epidemiologia , Carcinoma de Célula de Merkel/terapia , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/terapia , Espanha/epidemiologiaRESUMO
Most renal calculi can be classified using well-established criteria in a manner that reflects both composition and fine structure under specific pathophysiological conditions. However, when a large patient population is considered, rare renal calculi invariably appear, some of which have never been classified; careful study is required to establish stone etiology in such cases. The patient in the present case report formed two types of calculi. One was attached on the wall of the renal pelvis near the ureter and part of the calculus was embedded inside pelvic renal tissue. The calculus developed on an ossified calcification located in the pelvis tissue. Current knowledge on the development of calcification in soft tissues suggests a pre-existing injury as an inducer of its development. A mechanism of calculus formation is proposed. The second stone was a typical jack-stone calculus.
Assuntos
Oxalato de Cálcio/análise , Cálculos Renais/química , Pelve Renal , Adulto , Humanos , MasculinoRESUMO
We present a 44-year-old man with multiple flat papules over a tattoo, diagnosed with acquired verruciform epidermodysplasia (EV). The lesions completely disappeared after 3 sessions of photodynamic therapy (PDT) with topical methyl aminolevulinate. PDT could be considered a treatment of choice in human papillomavirus lesions located over tattoos since it resolves the lesions while preserving the integrity of the design.
Assuntos
Fotoquimioterapia , Tatuagem , Verrugas , Adulto , Humanos , Masculino , Papillomaviridae , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Verrugas/tratamento farmacológicoRESUMO
Tattoo complications are an increasing reason for dermatological consultation in recent years, becoming a therapeutic challenge in some cases. We present a case of a suppurative granulomatous reaction in a tattoo resistant to oral antibiotic and topical corticosteroid treatment that resolved after four sessions of photodynamic therapy (PDT) with methyl aminolevulinate, possibly due to its anti-inflammatory and antimicrobial action, with an excellent aesthetic result. We suggest that the clinical utility of PDT may be expanded to treatment of tattoo complications, as well as in cutaneous infections of unknown microorganisms resistant to antibiotics.
Assuntos
Fotoquimioterapia , Tatuagem , Administração Tópica , Ácido Aminolevulínico , Anti-Inflamatórios , Humanos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Tatuagem/efeitos adversosRESUMO
Non-small-cell lung cancer (NSCLC) is characterized by severe resistance to chemotherapy. Here, we demonstrate that A549 adenocarcinoma cells permanently differentiate with the antimetabolites methotrexate (MTX) and gemcitabine (GE) when blocking the resistance mechanism that normally counteracts this process. MTX (1-10 microM) and GE (1 microM) induced growth arrest accompanied by sustained extracellular signal-regulated kinase (ERK1/2) phosphorylation and moderate reduction of c-Myc levels after 96 h, whereas only a low percentage of the cells differentiated. Combination with the mitogen-activated protein kinase kinase (MEK) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis-(methylthio)butadiene (U0126) reduced MTX- or GE-induced ERK1/2 over-phosphorylation, nearly abolished c-Myc expression, and provoked radical morphological changes in all cells. Besides the appearance of multilamellar bodies and intracellular cytokeratin reorganization, modulation of molecular markers occurred in a manner consistent with differentiation (gelsolin, +300%; surfactant protein A and C, -70%). Similar to U0126, c-Myc inactivation with specific small interfering RNA initiated differentiation only in the presence of MTX, demonstrating that inhibition of the mitogen-activated protein kinase/ERK pathway alone or down-regulation of c-Myc is not sufficient to induce this process. It is noteworthy that withdrawal of antitumoral drugs and U0126 neither reversed differentiation nor reactivated proliferation. Our results reveal that maintenance of a certain threshold of c-Myc expression through sustained ERK1/2 activation represents a molecular mechanism that confers resistance to antimetabolite-induced differentiation in A549 cells, and provide a novel molecular basis for therapeutic strategies based on irreversible differentiation of cancer cells using conventional chemotherapeutic antimetabolites in combination with inhibitors of the MEK/ERK pathway or c-Myc.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desoxicitidina/análogos & derivados , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Metotrexato/farmacologia , Fatores de Transcrição/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/antagonistas & inibidores , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metotrexato/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , GencitabinaRESUMO
Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here.Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma.Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle.Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2 Clin Cancer Res; 24(21); 5239-49. ©2018 AACR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Gradação de Tumores , Estadiamento de Neoplasias , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/mortalidadeRESUMO
Silvery hair is a characteristic finding of 3 rare autosomal recessive disorders: Chédiak-Higashi syndrome (CHS), Elejalde syndrome (ES), and Griscelli syndrome (GS). We report the case of a 2-month-old male infant with transient silvery hair and generalized hypopigmentation of the skin and eyes who did not have one of these classic causative disorders. The patient was delivered at 35 weeks' gestation with congenital hydrops fetalis associated with a chromosomal abnormality (46,XY,add[2],[p23]), hypothyroidism, hypoproteinemia, and hypogammaglobulinemia. Over the course of follow-up, spontaneous brown repigmentation of the silvery hair was noted. We concluded that the silvery hair was induced by hypoproteinemia secondary to congenital hydrops fetalis.
Assuntos
Doenças do Cabelo/patologia , Hipopigmentação/patologia , Agamaglobulinemia/complicações , Aberrações Cromossômicas , Hipotireoidismo Congênito/complicações , Doenças do Cabelo/complicações , Humanos , Hidropisia Fetal , Hipopigmentação/complicações , Hipoproteinemia/complicações , Lactente , Masculino , Remissão EspontâneaAssuntos
Acantólise/diagnóstico , COVID-19/diagnóstico , Ictiose/diagnóstico , SARS-CoV-2/isolamento & purificação , Acantólise/sangue , Acantólise/imunologia , Acantólise/patologia , Biópsia , COVID-19/complicações , COVID-19/imunologia , COVID-19/virologia , Teste Sorológico para COVID-19 , Dermoscopia , Diagnóstico Diferencial , Exantema , Humanos , Ictiose/sangue , Ictiose/imunologia , Ictiose/patologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Pele/diagnóstico por imagem , Pele/patologiaRESUMO
IMPORTANCE: Epithelioid sarcomalike (pseudomyogenic) hemangioendothelioma (ES-H) is a recently described and little-known vascular neoplasm that frequently presents with dermatologic lesions. Histopathologic characterization includes sheets or fascicles of plump, spindled and epithelioid, rhabdomyoblastlike neoplastic cells involving the dermis and often extending to subcutaneous tissue. Immunohistochemical analysis reveals neoplastic cells that show a constant immunophenotype characterized by immunoreactivity for cytokeratins and endothelial markers. OBSERVATIONS: We described the clinical, histopathologic, and immunohistochemical features of 2 cases of cutaneous ES-H. Clinical examination revealed multifocal lesions that consisted of erythematous nodules on the leg and foot in case 1 and small perioral papules in case 2. Neoplastic cells had a rhabdomyoblastic appearance, with large nuclei and ample eosinophilic cytoplasm. Immunohistochemical analysis revealed expression of cytokeratin AE1/AE3, CD31, ERG, and FLI-1, with focal and weak positivity for CAM 5.2 and smooth muscle actin. The nuclei of neoplastic cells showed intact expression of INI-1. This immunoprofile, especially the ERG positivity, demonstrated the endothelial nature of proliferating cells. CONCLUSIONS: We recommend adding the low-grade neoplasm ES-H to the large list of cutaneous vascular proliferations. Dermatologists should be aware of this low-grade cutaneous vascular tumor.
Assuntos
Hemangioendotelioma Epitelioide/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Feminino , Hemangioendotelioma Epitelioide/metabolismo , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Masculino , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/cirurgia , Adulto JovemRESUMO
The very high mortality rate of gliomas reflects the unmet therapeutic need associated with this type of brain tumor. We have discovered that the plasma membrane fulfills a critical role in the propagation of tumorigenic signals, whereby changes in membrane lipid content can either activate or silence relevant pathways. We have designed a synthetic fatty acid, 2-hydroxyoleic acid (2OHOA), that specifically activates sphingomyelin synthase (SGMS), thereby modifying the lipid content of cancer cell membranes and restoring lipid levels to those found in normal cells. In reverting, the structure of the membrane by activating SGMS, 2OHOA inhibits the RAS-MAPK pathway, which in turn fails to activate the CCND (Cyclin D)-CDK4/CDK6 and PI3K-AKT1 pathways. The overall result in SF767 cancer cells, a line that is resistant to apoptosis, is the sequential induction of cell cycle arrest, cell differentiation and autophagy. Such effects are not observed in normal cells (MRC-5) and thus, this specific activation of programmed cell death infers greater efficacy and lower toxicity to 2OHOA than that associated with temozolomide (TMZ), the reference drug for the treatment of glioma.
Assuntos
Autofagia/efeitos dos fármacos , Glioma/patologia , Ácidos Oleicos/farmacologia , Esfingomielinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacosRESUMO
Trabectedin, a naturally occurring substance isolated from the Caribbean marine invertebrate Ecteinascidia turbinata, is the active compound of the antitumor drug Yondelis®. The mechanism of action of Trabectedin has been attributed to interactions with the minor groove of the DNA double helix, thereby affecting transcription of different genes involved in DNA repair and thus facilitating lethal DNA strand breaks. Nevertheless, the existence of other clinically important molecular mechanisms has not yet been fully explored. In this paper we demonstrate how Yondelis®, apart from activating the caspase-8-dependent cascade of apoptosis, sensitizes cancer cells to Fas-mediated cell death at achievable concentrations similar to those found in the plasma of patients. In addition we show that the facilitated apoptosis activated through the Fas death receptor, is associated with a significant increase of membrane Fas/FasL, as well as the modulation of accessory proteins regulating this route, such as FLIP (L) or Akt. Thus, our results propose that the sensitization of the death receptor pathway is an essential mechanism amplifying the cytotoxic properties of Yondelis® that could explain the hepatotoxicity observed in patients treated with this drug. Finally, we also show how the use of dexamethasone as a prophylactic agent that protects against hepatotoxicity induced by Yondelis® may also inhibit some of the cytotoxic properties described in this work. The study of this important mechanism of action should set up the basis for reassessing clinical therapy with Yondelis® in order to improve antitumor treatment outcome.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Dioxóis/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Receptor fas/metabolismo , Anticorpos/imunologia , Anticorpos/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/antagonistas & inibidores , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Dioxóis/efeitos adversos , Dioxóis/antagonistas & inibidores , Proteína Ligante Fas/metabolismo , Humanos , Fígado/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/química , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/antagonistas & inibidores , Trabectedina , Receptor fas/imunologiaAssuntos
Infecções Bacterianas/terapia , Estimulação Cardíaca Artificial/efeitos adversos , Remoção de Dispositivo , Bloqueio Cardíaco/terapia , Marca-Passo Artificial/efeitos adversos , Idoso , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/microbiologia , Remoção de Dispositivo/efeitos adversos , Remoção de Dispositivo/métodos , Desenho de Equipamento , Bloqueio Cardíaco/diagnóstico , Humanos , Masculino , Radiografia Intervencionista , Resultado do Tratamento , Insuficiência da Valva Tricúspide/diagnóstico , Insuficiência da Valva Tricúspide/etiologiaRESUMO
Most drugs currently used for human therapy interact with proteins, altering their activity to modulate the pathological cell physiology. In contrast, 2-hydroxy-9-cis-octadecenoic acid (Minerval) was designed to modify the lipid organization of the membrane. Its structure was deduced following the guidelines of the mechanism of action previously proposed by us for certain antitumor drugs. The antiproliferative activity of Minerval supports the above-mentioned hypothesis. This molecule augments the propensity of membrane lipids to organize into nonlamellar (hexagonal H(II)) phases, promoting the subsequent recruitment of protein kinase C (PKC) to the cell membrane. The binding of the enzyme to membranes was marked and significantly elevated by Minerval in model (liposomes) and cell (A549) membranes and in heart membranes from animals treated with this drug. In addition, Minerval induced increased PKCalpha expression (mRNA and protein levels) in A549 cells. This drug also induced PKC activation, which led to a p53-independent increase in p21(CIP) expression, followed by a decrease in the cellular concentrations of cyclins A, B, and D3 and cdk2. These molecular changes impaired the cell cycle progression of A549 cells. At the cellular and physiological level, administration of Minerval inhibited the growth of cancer cells and exerted antitumor effects in animal models of cancer without apparent histological toxicity. The present results support the potential use of Minerval and related compounds in the treatment of tumor pathologies.