Assuntos
Antifúngicos , Axila , Paracoccidioidomicose , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Pele/patologia , Pele/microbiologiaRESUMO
BACKGROUND: COPD due to exposure to combustible biomass is an increasingly recognized phenotype, particularly among women who use traditional ovens, known as 'Tabouna', for baking bread. This paper aims to investigate the clinical and functional characteristics of COPD in Tunisian female patients attributed to the use of 'Tabouna'. METHODS: A retrospective single-center cohort study was conducted on patients recruited from the Department of Respiratory Disease at A. Mami Hospital, who were diagnosed with COPD between January 2014 and December 2022. The diagnosis of COPD adhered to the standards defined in GOLD 2022. RESULTS: Out of the 95 women included in the study, 48 (50.5%) were exposed to tobacco smoke, while 47 (49.5%) were exposed to the 'Tabouna'. The median age was 70.4 ± 11.5 years, ranging from 40 to 95 years. Patients exposed to biomass were notably older, with a median age of 75.4 compared to 64.6 (p = 0.04). A significant association was observed between COPD and biomass smoke exposure, both in women residing in rural and urban areas (p = 0.006). The frequency of patients exposed to biomass with comorbidities was higher than in the group exposed to tobacco, but only hypertension showed statistically significant results (p = 0.01). Tobacco smoke induced more impairment in lung function than biomass in the group with FEV1 ≤ 30% (p = 0.04). Long-acting muscarinic antagonists were more commonly prescribed to smokers (p = 0.04). Serious complications such as chronic respiratory failure and intensive care admissions were similar in both groups (p = 0.8 and 0.4). CONCLUSIONS: COPD in women after exposure to the 'Tabouna' was observed in older patients and characterized by delayed diagnosis. Despite these clinical differences, poor COPD outcomes were similar in both groups.
RESUMO
Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-ß1 (TGF-ß1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-ß expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-ß expression in vivo, the blockade of TGF-ß-induced myofibroblast differentiation, and the reduction of TGF-ß-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.
Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Telomerase , Camundongos , Animais , Catalase/metabolismo , Telomerase/metabolismo , Remodelação das Vias Aéreas , Fumar Cigarros/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Fibroblastos/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Colágeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo , FibroseRESUMO
BACKGROUND: Mineralogical analyses of bronchoalveolar lavage (BAL) may help in assessing past exposure to mineral particles. However, their interpretation relies on their quality, meaning their representativeness of the alveolar compartment. The aim of this study was to find predictive factors of BAL samples quality allowing a reliable mineralogical analysis. METHODS: All BAL samples analyzed between 2018 and 2020 in the Asbestos Fibers and Particles Laboratory from Paris City were included. They were read by an experienced cyto-pathologist and validated according to their representativeness of the alveolar region compartment. Univariate and stratified analyses were conducted to identify factors associated with the samples' cytological quality. RESULTS: On the 780 samples included, 64.4% were deemed of good cytological quality and 17.9% were not interpretable. Injected volume and BAL yield (recovery volume on injected volume ratio) were associated with cytological quality. Injecting at least 100mL with a ≥60% yield or injecting at least 150mL with a ≥30% yield allowed having a good proportion of BAL with sufficient cytological quality. CONCLUSIONS: Injected volume greater than 100mL with sufficient BAL yield are essential factors to ensure a reliable mineralogical analysis of BAL samples.
Assuntos
Amianto , Amianto/análise , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , Laboratórios , Minerais/análiseRESUMO
BACKGROUND AND OBJECTIVE: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations. METHODS: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network. RESULTS: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation. CONCLUSION: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.
Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Exorribonucleases , Humanos , Fibrose Pulmonar Idiopática/genética , Doenças Pulmonares Intersticiais/genética , Mutação/genética , Estudos RetrospectivosRESUMO
Chronic interstitial lung abnormalities have been described in sickle cell disease (SCD) and attributed to repetitive episode of acute chest syndrome. We report a series of 22 cases of diffuse cystic lung disease in SCD with a case-control study to hunt for mechanism. On pathological analysis of a surgical lung biopsy of the index case, the bronchioles had the appearance of constrictive bronchiolitis. Pulmonary function test results revealed lower forced expiratory flow from 25% to 75% of vital capacity in cases versus controls. These findings suggest a bronchiolar mechanism that was not associated with more acute chest syndrome.
Assuntos
Anemia Falciforme , Doenças Pulmonares Intersticiais , Anemia Falciforme/complicações , Estudos de Casos e Controles , Humanos , Pulmão/diagnóstico por imagem , Capacidade VitalRESUMO
Biomarkers of disease severity might help with individualizing the management of patients with acute respiratory distress syndrome (ARDS). During sepsis, a sustained decreased expression of the antigen-presenting molecule human leucocyte antigen-DR (HLA-DR) on circulating monocytes is used as a surrogate marker of immune failure. This study aimed at assessing whether HLA-DR expression on alveolar monocytes in the setting of a severe lung infection is associated with their functional alterations. BAL fluid and blood from immunocompetent patients with pneumonia-related ARDS admitted between 2016 and 2018 were isolated in a prospective monocentric study. Alveolar and blood monocytes were immunophenotyped using flow cytometry. Functional tests were performed on alveolar and blood monocytes after in vitro lipopolysaccharide (LPS) stimulation. Phagocytosis activity and intracellular tumor necrosis factor (TNF) production were quantified using fluorochrome-conjugated-specific antibodies. Ten ARDS and seven non-ARDS control patients were included. Patients with pneumonia-related ARDS exhibited significantly lower HLA-DR expression both on circulating (p < 0.0001) and alveolar (p = 0.0002) monocytes. There was no statistically significant difference observed between patient groups (ARDS vs. non-ARDS) regarding both alveolar and blood monocytes phagocytosis activity. After LPS stimulation, alveolar (p = 0.027) and blood (p = 0.005) monocytes from pneumonia-related ARDS patients had a significantly lower intracellular TNF expression than non-ARDS patients. Monocytes from pneumonia-related ARDS patients have a deactivated status and an impaired TNF production capacity but display potent phagocytic activity. HLA-DR level expression should not be used as a surrogate marker of the phagocytic activity or the TNF production capacity of alveolar monocytes.
Assuntos
Monócitos/patologia , Pneumonia/complicações , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório/complicações , Adulto , Idoso , Antígeno B7-H1/metabolismo , Líquido da Lavagem Broncoalveolar , Escherichia coli/fisiologia , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fagocitose , Pneumonia/sangue , Alvéolos Pulmonares/metabolismo , Síndrome do Desconforto Respiratório/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: etiological investigations are not done for all adult patients with bronchiectasis because of the availability and interpretation of tests. The aim of the study was to elaborate a score to identify patients at high risk of having cystic fibrosis or primary ciliary dyskinesia (CF/PCD), which require appropriate management. METHODS: diagnostic work-ups were carried out on a French monocenter cohort, and results were subjected to logistic-regression analyses to identify the independent factors associated with CF/PCD diagnosis and, thereby, elaborate a score to validate in a second cohort. RESULTS: among 188 patients, 158 had no obvious diagnosis and were enrolled in the algorithm-construction group. In multivariate analyses, age at symptom onset (8.69 (2.10-35.99); p = 0.003), chronic ENT symptoms or diagnosed sinusitis (10.53 (1.26-87.57); p = 0.03), digestive symptoms or situs inversus (5.10 (1.23-21.14); p = 0.025), and Pseudomonas. aeruginosa and/or Staphylococcus aureus isolated from sputum (11.13 (1.34-92.21); p = 0.02) are associated with CF or PCD. Receiver operating characteristics curve analysis, using a validation group of 167 patients with bronchiectasis, confirmed the score's performance with AUC 0.92 (95% CI: 0.84-0.98). CONCLUSIONS: a clinical score may help identify adult patients with bronchiectasis at higher risk of having CF or PCD.
Assuntos
Azetidinas/efeitos adversos , Granuloma/induzido quimicamente , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Sarcoidose/induzido quimicamente , Vemurafenib/efeitos adversos , Idoso , Feminino , Granuloma/patologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Sarcoidose/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaAssuntos
Linfoma Cutâneo de Células T/diagnóstico , Pitiríase Liquenoide/diagnóstico , Pitiríase Liquenoide/patologia , Neoplasias Cutâneas/diagnóstico , Pele/patologia , Linfócitos T CD8-Positivos/patologia , Diagnóstico Diferencial , Feminino , Febre/etiologia , Humanos , Pessoa de Meia-Idade , Necrose/etiologia , Pitiríase Liquenoide/complicações , Úlcera Cutânea/etiologiaRESUMO
BACKGROUND: Mycoplasma pneumoniae infection has been documented in erythema multiforme (EM) and Stevens-Johnson syndrome-toxic epidermal necrosis (SJS-TEN). Clinical aspects of M pneumoniae-related EM have been poorly described in the literature. OBJECTIVE: To highlight differences between M pneumoniae EM and non-M pneumoniae EM. METHODS: This single-center, retrospective cohort study included all patients admitted to our dermatology department for EM during 2000-2015. We compared epidemiologic, clinical, and histologic data and follow-up for M pneumoniae EM and non-M pneumoniae EM cases. RESULTS: Thirty-three patients with M pneumoniae EM were compared with 100 patients with non-M pneumoniae EM. Disease onset in winter was more frequent with M pneumoniae EM (P = .003). Acrally distributed lesions (32% vs 88%, P < .0001) and typical targets (45% vs 74%, P = .01) were less common in M pneumoniae EM than non-M pneumoniae EM. Multiple (≥2) mucousal membrane involvement was more frequent in M pneumoniae EM than non-M pneumoniae EM (97% vs 60%; P < .0001), as were mucosal and respiratory tract sequelae (P < .05). The mean hospital stay was longer with M pneumoniae EM patients: 9.5 days versus 5.1 days (P = .0002). A TEN-like pattern was observed in all 14 (100%) M pneumoniae EM skin biopsies versus 10 of 27 (48%) non-M pneumoniae EM biopsies (P < .001). LIMITATIONS: The retrospective design. CONCLUSION: M pneumoniae EM has a distinctive presentation compared with non-M pneumoniae EM, with more diffuse and atypical targets, more mucositis and respiratory tract sequelae. Histologic data show a TEN-like pattern in all M pneumoniae EM skin samples.
Assuntos
Eritema Multiforme/microbiologia , Eritema Multiforme/patologia , Mycoplasma pneumoniae/patogenicidade , Pneumonia por Mycoplasma/epidemiologia , Pneumonia por Mycoplasma/patologia , Centros Médicos Acadêmicos , Adulto , Fatores Etários , Biópsia por Agulha , Estudos de Coortes , Eritema Multiforme/epidemiologia , Feminino , França , Humanos , Imuno-Histoquímica , Incidência , Masculino , Pessoa de Meia-Idade , Mucosite/epidemiologia , Mucosite/microbiologia , Mucosite/patologia , Pneumonia por Mycoplasma/fisiopatologia , Prognóstico , Valores de Referência , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
A 71-year-old-man was transferred to our hospital in November 2012 for a bronchial artery embolization in the context of recurrent blood clots obstructing the left lower bronchus. Since June 2012, he had been explored for a cystic hypermetabolic lesion of the entire left lobe, and underwent 3 bronchoscopies and 2 computed tomography scan-guided biopsies, with no success. A fourth bronchoscopy enabled the extraction of a large blood clot (8×1.5 cm) that obstructed the left main bronchus. The pathologic examination of the mucosal biopsy samples was inconclusive, whereas the cytologic examination of the blood clot revealed myxoid liposarcoma. Liposarcomas are the most common histologic types of soft-tissue sarcomas. They preferentially metastasize to the lungs and can appear as cystic mass. Bronchial obstruction by blood clots is not a rare finding on bronchoscopy, their main problem is their removal which could require rigid bronchoscope and large forceps. However, bronchial blood clot containing tumoral process had never been reported before. In conclusion, this case conveys 2 messages. First, pulmonary metastasis of myxoid liposarcoma can appear as cyst secondary to endobronchial tumoral growth. Second, endobronchial blood clots should always be sent for pathologic analysis.
Assuntos
Neoplasias Brônquicas/diagnóstico , Lipossarcoma Mixoide/diagnóstico , Trombose/diagnóstico , Idoso , Broncoscopia , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
BACKGROUND: Various late-onset noninfectious pulmonary complications may occur after allogeneic hematopoietic stem cell transplantation (HSCT). Interstitial lung diseases (ILD) are often overlooked, and few data are available. METHODS: We retrospectively analyzed the clinical features, pulmonary function tests, radiological features and outcomes of allogeneic HSCT recipients who were diagnosed with a noninfectious ILD and were managed in our center between 2001 and 2010. RESULTS: Forty patients were analyzed. The median time from transplant to ILD was 11.3 months. The donor hematopoietic stem cell source was peripheral blood stem cells in 75% of the cases. Seventy percent of the patients had extra-thoracic chronic graft versus host disease at ILD diagnosis. We identified two lung computed tomography (CT) scan patterns according to the predominance of ground glass opacities or alveolar consolidations. Restrictive ventilatory defect was the main pulmonary function pattern. Lung histology was available for seven patients and showed diffuse alveolar damage, non-specific interstitial pneumonia, organizing pneumonia or lymphoid interstitial pneumonia. Thirty-five patients (87.5%) were treated with systemic steroids. Thirteen patients died (32.5%), 10 of respiratory failure. The median survival rate at 24 months was 61%. CONCLUSION: This study highlights the existence of noninfectious post-allogeneic HSCT ILD and provides new insights into the characteristics of these illnesses.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Adulto , Fatores Etários , Idade de Início , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c(+)CD11b(+)Ly6C(hi) cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.
Assuntos
Antraciclinas/administração & dosagem , Células Apresentadoras de Antígenos/imunologia , Antineoplásicos/administração & dosagem , Células Dendríticas/imunologia , Neoplasias Experimentais/imunologia , Transferência Adotiva , Animais , Antraciclinas/efeitos adversos , Antígenos Ly/metabolismo , Antígenos de Neoplasias/imunologia , Antineoplásicos/efeitos adversos , Apoptose , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Precursoras de Granulócitos/imunologia , Imunidade Celular , Camundongos , Camundongos Endogâmicos C57BL , Células Precursoras de Monócitos e Macrófagos/imunologia , Neoplasias Experimentais/tratamento farmacológico , Nucleotidases/metabolismo , Receptores Purinérgicos/metabolismoRESUMO
Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Vitamina B 6/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piridoxal Quinase/biossíntese , Piridoxal Quinase/genética , Taxa de Sobrevida , Vitamina B 6/genéticaRESUMO
Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the inhibition of the plasma membrane Na(+)- and K(+)-dependent adenosine triphosphatase (Na(+)/K(+)-ATPase). CGs exacerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate syngeneic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Glicosídeos Cardíacos/farmacologia , Glicosídeos Cardíacos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Técnicas Biossensoriais , Linhagem Celular Tumoral , Digoxina/farmacologia , Digoxina/uso terapêutico , Humanos , Camundongos , Neoplasias/metabolismo , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , OxaliplatinaRESUMO
The genetic or functional inactivation of p53 is highly prevalent in human cancers. Using high-content videomicroscopy based on fluorescent TP53(+/+) and TP53(-/-) human colon carcinoma cells, we discovered that SP600125, a broad-spectrum serine/threonine kinase inhibitor, kills p53-deficient cells more efficiently than their p53-proficient counterparts, in vitro. Similar observations were obtained in vivo, in mice carrying p53-deficient and -proficient human xenografts. Such a preferential cytotoxicity could be attributed to the failure of p53-deficient cells to undergo cell cycle arrest in response to SP600125. TP53(-/-) (but not TP53(+/+) ) cells treated with SP600125 became polyploid upon mitotic abortion and progressively succumbed to mitochondrial apoptosis. The expression of an SP600125-resistant variant of the mitotic kinase MPS1 in TP53(-/-) cells reduced SP600125-induced polyploidization. Thus, by targeting MPS1, SP600125 triggers a polyploidization program that cannot be sustained by TP53(-/-) cells, resulting in the activation of mitotic catastrophe, an oncosuppressive mechanism for the eradication of mitosis-incompetent cells.
Assuntos
Antracenos/farmacologia , Antineoplásicos/farmacologia , Proteína Supressora de Tumor p53/deficiência , Animais , Antracenos/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Microscopia de Vídeo/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The success of some chemo- and radiotherapeutic regimens relies on the induction of immunogenic tumor cell death and on the induction of an anticancer immune response. Cells succumbing to immunogenic cell death undergo specific changes in their surface characteristics and release pro-immunogenic factors according to a defined spatiotemporal pattern. This stimulates antigen presenting cells such as dendritic cells to efficiently take up tumor antigens, process them, and cross-prime cytotoxic T lymphocytes, thus eliciting a tumor-specific cognate immune response. Such a response can also target therapy-resistant tumor (stem) cells, thereby leading, at least in some instances, to tumor eradication. In this review, we shed some light on the molecular identity of the factors that are required for cell death to be perceived as immunogenic. We discuss the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, the most abundant intracellular metabolite, ATP, and the most abundant non-histone chromatin-binding protein, HMGB1, can determine whether cell death is immunogenic as they appear on the surface or in the microenvironment of dying cells.