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1.
Jpn J Clin Oncol ; 51(1): 37-44, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33147606

RESUMEN

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit.


Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Compuestos Organofosforados/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Quinasa de Linfoma Anaplásico/análisis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología
2.
J Surg Oncol ; 123(1): 322-331, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32989763

RESUMEN

INTRODUCTION: Few studies have investigated the impact of active surveillance on pathological outcome ground-glass nodules (GGNs). We focused on GGNs that needed preoperative localization before resection and compared the pathological results between GGNs that underwent early resection or active surveillance. METHODS: We retrospectively reviewed data of resected GGNs between January 2017 and December 2018. GGNs were classified by early resection (Group A) and active surveillance (Group B). Group B was subclassified as no (Group B1) and with (Group B2) growth, and intergroup comparison of pathological results was undertaken. RESULTS: In total, 509 GGNs (124, 275, and 110 in Groups A, B1, and B2, respectively) were included. Malignancy (primary lung cancer) ratios were 68% and 72% in Groups A and B (p = .312) and 65% and 92% in Groups B1 and B2, respectively (p < .001). The ratios of invasive carcinoma were 21.4%, 9.6%, and 35.6% in Groups A, B1, and B2, respectively. Predictors for invasive carcinoma included history of lung cancer, GGN size ≥ 10 mm, solid size ≥ 6 mm, and GGN growth. CONCLUSIONS: The pathological findings were similar for GGNs in the early resection and active surveillance groups. However, rates of malignancy and invasive carcinoma increased in the group that manifested growth during active surveillance.


Asunto(s)
Neoplasias Pulmonares/patología , Nódulo Pulmonar Solitario/patología , Tomografía Computarizada por Rayos X/métodos , Espera Vigilante/métodos , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/cirugía
3.
J Surg Oncol ; 123(1): 332-341, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33002203

RESUMEN

BACKGROUND: The aim of this study was to investigate the clinicopathological and prognostic features of operable non-small cell lung cancer (NSCLC) patients with diabetes mellitus (DM). METHODS: A total of 1231 surgically resected NSCLC patients were retrospectively reviewed. Clinicopathological characteristics were compared between patients with DM (DM group, n = 139) and those without DM (non-DM group, n = 1092). The clinical factors associated with postoperative complications and prognostic factors were identified. RESULTS: The DM group had distinct clinicopathological features. No significant differences in histological invasiveness or stage were found. The presence and control status of DM were independent predictors of postoperative complications. No significant differences in recurrence-free survival or cancer-specific survival were observed; however, the DM group had worse overall survival (OS). The DM group had a higher number of deaths from other diseases than the non-DM group, and these patients had significantly higher postoperative hemoglobin A1c levels than patients with cancer-related death. CONCLUSION: The presence and control status of preoperative DM are useful predictors of both postoperative complications and OS in operable NSCLC patients. Concomitant diabetes-related complications have a negative effect on long-term survival in diabetic NSCLC patients, and long-term glycemic control is important to prolong OS.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Complicaciones de la Diabetes/patología , Diabetes Mellitus/fisiopatología , Neoplasias Pulmonares/patología , Complicaciones Posoperatorias/patología , Anciano , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Complicaciones de la Diabetes/epidemiología , Complicaciones de la Diabetes/cirugía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Japón/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/cirugía , Masculino , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
4.
Jpn J Clin Oncol ; 51(1): 114-119, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33094807

RESUMEN

BACKGROUND: Solid component size on thin-section computed tomography is used for T-staging according to the eighth edition of the Tumor Node Metastasis classification of lung cancer. However, the feasibility of using the solid component to measure clinical T-factor remains controversial. METHODS: We evaluated the feasibility of measuring the solid component in 859 tumours, which were suspected cases of primary lung cancers, requiring surgical resection regardless of the procedure or clinical stage. After excluding 126 pure ground-glass opacity tumours and 450 solid tumours, 283 part-solid tumours were analysed to determine the frequency of cases where the measurement of the solid portion was difficult along with the associated cause. Pathological invasiveness was also evaluated. RESULTS: The solid portion of 10 lesions in 283 part-solid nodules was difficult to measure due to an underlying lung disease (emphysema and pneumonitis). The solid portion of 62 lesions (21.9%) without emphysema and pneumonitis was difficult to measure due to imaging features of the tumours. Among the 62 patients, five had no malignancy and one with a tumour size of 33 mm had nodal metastasis. There were 56 lesions with a tumour size of ≤30 mm, wherein nodal metastases, vascular and/or lymphatic invasions were not observed. CONCLUSION: For one-fifth of the part-solid tumours, measurement of the solid component was difficult. Moreover, these lesions had low invasiveness, especially in T1. The measurement of the solid portion and the classification of T1 in 1-cm increments may be complex.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/cirugía , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos
5.
Life Sci ; 265: 118768, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33217443

RESUMEN

Non-small cell lung cancer (NSCLC) patients have a lower 5-year survival rate, and the distant tumor metastasis and drug resistance are the main reasons for the high mortality. RECQL5, a member of RecQ helicases family, has been linked to tumorigenesis of various cancers expect NSCLC. In the current study, analysis with the Cancer Genome Atlas (TCGA) dataset showed that the level of RECQL5 was elevated in LUAD (Lung Adenocarcinoma) and LUSC (lung squamous carcinomas), two major subtypes of NSCLC, which was confirmed by immunohistochemistry staining on Tissue array slides. The level of RECQL5 was also elevated in NSCLC cell lines. Further, Kaplan-Meier analysis of TCGA dataset suggested that the up-regulated RECQL5 was associated with poor prognosis of LUAD, but not with that of LUSC. Knockdown of RECQL5 significantly inhibited the invasion and migration of NSCLC cells, and suppressed epithelial-mesenchymal transition (EMT) as indicated by the changes of EMT-related proteins, while overexpression of RECQL5 displayed reverse effects. Lung metastasis was also suppressed by RECQL5 knockdown. Additionally, the addition of Akt inhibitor LY294002 reversed the effects of RECQL5 overexpression on cell migration, invasion and EMT. Moreover, knockdown of RECQL5 increased the apoptosis of cisplatin-resistant A549 cell line (A549/DDP) caused by cisplatin treatment. In summary, RECQL5 contributed to the metastasis of NSCLC and assisted NSCLC cells incompletely response to cisplatin therapy, and could be considered as a biomarker or clinical target for NSCLC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/uso terapéutico , Neoplasias Pulmonares/metabolismo , RecQ Helicasas/metabolismo , Animales , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Reacción en Cadena en Tiempo Real de la Polimerasa , RecQ Helicasas/fisiología
6.
Phytomedicine ; 80: 153384, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33113507

RESUMEN

BACKGROUND: Ling Zhi-8 (LZ-8) and GMI are two fungal immunomodulatory proteins (FIPs) with a similar structure and amino acid sequence and are respectively obtained from the medicinal mushroom Ganoderma lucidum and Ganoderma microsporum. They present the anti-cancer progression and metastasis. We previously demonstrated that LZ-8 reduces the tumor progression in lung cancer LLC1 cell-bearing mouse. However, it is unclear whether these FIPs induce changes in the protein expression profile in cancer cells and the mechanism for such a process is not defined. PURPOSE: This study determines the changes in the proteomic profile for tumor lesions of LLC1 cell-bearing mouse received with LZ-8 and the potential mechanism for FIPs in anti-lung cancer cells. METHODS: The proteomic profile of tumor lesions was determined using two-dimensional electrophoresis and a LTQ-OrbitrapXL mass spectrometer (LC-MS/MS). The biological processes and the signaling pathway enrichment analysis were performed using Ingenuity Pathway Analysis (IPA). The differentially expressed proteins were verified by Western blot. Cell viability was determined by MTT assay. Cell morphology was characterized using electron microscopy. Migration was detected using the Transwell assay. The apoptotic response was determined using Western blot and flow cytometry. RESULTS: Obtained results showed that 21 proteins in the tumor lesions exhibited differential (2-fold change, p < 0.05) expression between PBS and LZ-8 treatment groups. LZ-8-induced changes in the proteomic profile that may relate to protein degradation pathways. Specifically, three heat shock proteins (HSPs), HSP60, 70 and 90, were significantly downregulated in tumor lesions of LLC1-bearing mouse received with LZ-8. Both LZ-8 and GMI reduced the protein levels for these HSPs in lung cancer cells. Functional studies showed that they inhibited cell migration but effectively induced apoptotic response in LLC1 cells in vitro. In addition, the inhibitors of HSP60 and HSP70 effectively inhibited cell migration and decreased cell viability of LLC1 cells. CONCLUSIONS: LZ-8 induced changes in the proteomic profile of tumor lesions which may regulate the HSPs-related cell viability. Moreover, inhibition of HSPs may be related to the anti-lung cancer activity.


Asunto(s)
Proteínas Fúngicas/farmacología , Ganoderma/química , Proteínas de Choque Térmico/metabolismo , Factores Inmunológicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Regulación hacia Abajo/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos C57BL , Proteómica/métodos , Espectrometría de Masas en Tándem , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Phytomedicine ; 80: 153394, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33130472

RESUMEN

BACKGROUND: Programmed death-ligand 1 (PD-L1), which can be induced by interferon-gamma (IFN-γ) in the tumor microenvironment, is a critical immune checkpoint in cancer immunotherapy. Natural products which reduce IFN-γ-induced PD-L1 might be exert immunotherapy effect. Licochalcone A (LCA), a natural compound derived from the root of Glycyrrhiza inflata Batalin. (Fabaceae), was found to interfere IFN-γ-induced PD-L1. PURPOSE: The aim of this study is to further clarify the effect and the mechanism of LCA on inhibiting IFN-γ-induced PD-L1 in lung cancer cells. METHODS: The expression levels of PD-L1 were evaluated by flow cytometry, western blot and qRT-PCR. Click-iT protein synthesis assay and luciferase assay were used to identify the effect of LCA on protein synthesis. Jurkat T cell proliferation and apoptosis in the co-culture system were detected by flow cytometry. Flow cytometry was also applied to evaluate reactive oxygen species (ROS) generation. RESULTS: LCA downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in human lung cancer cells, regardless of inhibiting PD-L1 mRNA level or promoting its protein degradation. LCA decreased apoptosis and proliferative inhibition of Jurkat T cells caused by IFN-γ-induced PD-L1-expressing in A549 cells in the co-culture system. Strikingly, LCA was verified as a protein synthesis inhibitor, which reduced both cap-dependent and -independent translation. LCA inhibited PD-L1 translation, likely due to inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α pathway. Furthermore, LCA induced ROS generation in a time-dependent manner in lung cancer cells. N-acetyl-L-cysteine (NAC) not only revered ROS generation triggered by LCA but also restored IFN-γ-induced expression of PD-L1. Both the inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α axis triggered by LCA was restored by co-treatment with NAC. CONCLUSION: LCA abrogated IFN-γ-induced PD-L1 expression via ROS generation to abolish the protein translation, indicating that LCA has the potential to be applied in cancer immunotherapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antígeno B7-H1/metabolismo , Chalconas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis/efectos de los fármacos , Antígeno B7-H1/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Interferón gamma/metabolismo , Interferón gamma/farmacología , Células Jurkat , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
8.
Oncology ; 99(1): 1-14, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33221794

RESUMEN

BACKGROUND: Out-of-field tumor regression effects of radiation therapy (abscopal response) have been sporadically observed in the past, but they have only recently gained significant importance due to the use of innovative high-precision radiation delivery devices for the treatment of various cancers including non-small cell lung cancer (NSCLC). In this study, we provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with advanced NSCLC. SUMMARY: Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as MEDLINE via PubMed and Google Scholar. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Most studies describing the abscopal effects of radiation therapy in patients with advanced NSCLC have been in the form of either case reports or small cohort studies. Although the exact molecular mechanisms for the abscopal effect are yet to be established, current evidence indicates that tumor cell destruction induced by local radiation therapy releases tumor antigens, which stimulate the immune system of the host to activate the body's immune effector cells systemically and trigger the regression of distant nonirradiated cancer cells. These off-target antitumor effects of radiation therapy provide an opportunity to explore the use of the radiation therapy in combination with novel immunotherapy agents to maximize treatment outcomes in patients with advanced NSCLC and other cancers. Key Message: The findings suggest that radiation therapy has the ability to induce abscopal effects with an increased potential to boost these effects when it is used in combination with immunotherapy for the treatment of patients with advanced NSCLC and other cancers. Clinical trials investigating radiation therapy-induced abscopal effects may lead to a dramatic change in its use especially when it is combined with immunotherapy for the treatment of patients with advanced NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Neoplasias Pulmonares/radioterapia , Radioterapia/efectos adversos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Terapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , PubMed , Resultado del Tratamiento
9.
Life Sci ; 265: 118797, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33285162

RESUMEN

AIMS: Lung cancer was the most fatal malignancy, dominated the cancer related mortality list for years, and we tried to distinguish the lung adenocarcinoma patients at higher risk from those bearing lower therapy resistance and recurrence risk. MATERIALS: Patients information from clinical Sequencing Cohorts and from the Regional Medical Center of the Middle-West China were included. The whole-exome sequencing was analyzed for risk evaluation. KEY FINDINGS: We found that Smoking stimulated the oncogenic genes mutations, and the most frequently mutated genes of EGFR, KRAS, and TP53 (E/K/P) were identified. Different N stage affected the survival prognosis of patients bearing E/K/P mutations, but the T stage and AJCC stage did not. Radiation failed to prolong survival of phase II/III patients who didn't receive surgery. In those received surgery, radiation also failed to prolong survival of phase II/III patients. Radiation did not improve the prognosis in patients bearing E/K/P mutation burdens, whose differences were identified in gender or smoking-history classified groups. SIGNIFICANCE: Smoking status and history contributed to oncogenic mutation burdens associated therapy resistance, and the aggressive treatment, especially to radiation, may lead to worse therapy response to current and past smoking behavior.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Carcinogénesis/genética , Neoplasias Pulmonares/genética , Mutación/genética , Oncogenes/genética , Fumar/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/terapia , Anciano , Biomarcadores de Tumor/genética , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Mutación/efectos de los fármacos , Oncogenes/efectos de los fármacos , Fumar/patología , Fumar/terapia , Tasa de Supervivencia/tendencias , Resultado del Tratamiento
10.
Support Care Cancer ; 29(1): 117-125, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32318871

RESUMEN

PURPOSE: In REVEL, patients with advanced non-small-cell lung cancer (aNSCLC) and patients with increased tumor aggressiveness (rapid disease progression (RDP), platinum-refractory disease (PRD), and high symptom burden (HSB)) benefited from second-line treatment with ramucirumab plus docetaxel over placebo plus docetaxel. This post hoc analysis describes healthcare resource utilization (HCRU) associated with the treatment. METHODS: aNSCLC patients who had progressed during or after first-line platinum-based chemotherapy were randomized to receive docetaxel and either ramucirumab or placebo until disease progression, unacceptable toxicity, withdrawal, or death. HCRU included hospitalizations, transfusions, and concomitant medications. Categorical variables (counts and percentages) were compared using Fisher's exact test. Continuous variables (mean, standard deviation (SD), median, minimum, and maximum) were compared using the Wilcoxon rank sum test. RESULTS: Patient characteristics were largely similar between treatment arms. Within the intent-to-treat (ITT) population (n = 1253), the mean treatment duration was 19.7 and 16.9 weeks in the ramucirumab and control arms, respectively; 51.0% versus 54.9% of patients received subsequent anticancer therapy, respectively. Hospitalization rates were 41.9% versus 42.6% (p = 0.863), mean length of hospital stay was 14.5 days versus 11.3 days (p = 0.066), transfusion rates were 9.9% versus 12.3% (p = 0.206), and use of granulocyte colony-stimulating factors was 41.8% versus 36.6% (p = 0.063), respectively. No significant difference was observed in HCRU between treatment arms in both ITT population and in aggressive disease subgroups including RDP (n = 209), PRD (n = 360), and HSB (n = 497). CONCLUSION: In REVEL, the addition of ramucirumab to docetaxel did not increase HCRU among patients with aggressive aNSCLC disease. These results may help inform economic evaluation of treatment for patients with aNSCLC.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Aceptación de la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Platino (Metal)/uso terapéutico , Taxoides/uso terapéutico
11.
Gene ; 766: 145151, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32950635

RESUMEN

Smoking tobacco is the major hazard for lung cancer in Indian subcontinent especially men, compare to woman where, other important risk factors such as air pollutions are responsible. So, the aim of the study is to compare chronic smokers (CS) and non-smokers living in areas with air quality categorized as poor (AQI 201-300) or moderate (AQI 101-200). We measured the expression of non-small cell lung cancer (NSCLC) biomarkers;. IDH1, CEA, Cyfra21-1, and TPA through quantitative Real-Time PCR (qRT-PCR) and compared the levels of upregulation of the transcripts in stage IIIa NSCLC over control benign tissues among the smoking and AQI settings. Though the all biomarkers were significantly up-regulated in tumor tissues compared to control benign tissues, the fold change increase of IDH1 and CEA was highest in CS-poor/moderate AQI, followed by non-smokers-poor AQI and non-smokers moderate AQI. This indicates the aggressiveness and poor prognosis in CS living in either poor or moderate AQI areas. The level of Cyfra21-1 was lower in in the CS groups in comparison to non-smokers in the poor AQI area. This suggest higher Lung Squamous cell carcinoma histology in non-smokers living areas with poor AQI. Hence, we conclude that poor air quality can be as injurious for lung cancers as chronic smoking.


Asunto(s)
Antígenos de Neoplasias/genética , Antígeno Carcinoembrionario/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Isocitrato Deshidrogenasa/genética , Queratina-19/genética , Neoplasias Pulmonares/genética , Fumar/genética , Contaminación del Aire , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , No Fumadores , Pronóstico , Fumadores , Transcriptoma/genética
12.
Clin Imaging ; 69: 133-138, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32721848

RESUMEN

OBJECTIVES: The aim of this study was to delineate computed tomography (CT) features of stage IIIA non-small cell lung cancers on pre-treatment staging studies and identify features that could predict local recurrence after definitive concurrent chemoradiotherapy. MATERIALS AND METHODS: We retrospectively reviewed pre- and post-treatment CT scans for 91 patients with Stage IIIA non-small cell lung cancer undergoing definitive concurrent chemoradiotherapy. Pre-treatment CT qualitative features were evaluated by consensus. The primary endpoint was local recurrence as determined on post-treatment CT scans along with the radiotherapy fields. Local recurrence was defined as intrathoracic in-field and marginal as opposed to out-of-field failures. Competing risk regressions were used to examine associations between CT features and recurrence. RESULTS: The median follow-up was 51.5 months (range 2.4-111.2). Median overall survival was 25.6 months (95% CI: 20.4-30). At last follow-up, 72 (79.1%) patients had died, 48 (52.7%) had in-field recurrence, and 30 (32.9%) presented with out-of-field recurrence. On pre-treatment CT scans, tumors presenting as pulmonary consolidations (hazard ratio = 2.34, 95% CI: 1.05-5.22; p 0.038) were more likely to have in-field failure. Tumors with 50-100% necrosis (hazard ratio = 0.15, 95% CI: 0.02-1.06) were associated with decreased out-of-field failure (overall p = 0.038). However, these were rare features in our sample which limit the ability of these features to be associated with such outcomes. CONCLUSIONS: Pre-treatment CT features alone are limited in predicting locoregional recurrence. Larger studies using quantitative tools are needed to predict such outcomes.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Recurrencia Local de Neoplasia/diagnóstico por imagen , Estadificación de Neoplasias , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
13.
Phytomedicine ; 80: 153370, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33113504

RESUMEN

BACKGROUND: Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of ginkgetin and DDP in cancer therapy. METHODS: The promotion of DDP-induced anticancer effects by ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model. RESULTS: Ginkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells. CONCLUSION: This study is the first to report that ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biflavonoides/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Hemo-Oxigenasa 1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Células A549 , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Biflavonoides/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Receptores ErbB/genética , Ferroptosis/efectos de los fármacos , Ginkgo biloba/química , Hemo-Oxigenasa 1/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Hojas de la Planta/química , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Phytomedicine ; 80: 153355, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33039730

RESUMEN

BACKGROUND: Lung cancer has the highest incidence and cancer-related mortality of all cancers worldwide. Its treatment is focused on molecular targeted therapy. c-MET plays an important role in the development and metastasis of various human cancers and has been identified as an attractive potential anti-cancer target. Podophyllotoxin (PPT), an aryltetralin lignan isolated from the rhizomes of Podophyllum species, has several pharmacological activities that include anti-viral and anti-cancer effects. However, the mechanism of the anti-cancer effects of PPT on gefitinib-sensitive (HCC827) or -resistant (MET-amplified HCC827GR) non-small cell lung cancer (NSCLC) cells remains unexplored. PURPOSE: In the present study, we investigated the underlying mechanisms of PPT-induced apoptosis in NSCLC cells and found that the inhibition of c-MET kinase activity contributed to PPT-induced cell death. METHODS: The regulation of c-MET by PPT was examined by pull-down assay, ATP-competitive binding assay, kinase activity assay, molecular docking simulation, and Western blot analysis. The cell growth inhibitory effects of PPT on NSCLC cells were assessed using the MTT assay, soft agar assay, and flow cytometry analysis. RESULTS: PPT could directly interact with c-MET and inhibit kinase activity, which further induced the apoptosis of HCC827GR cells. In contrast, PPT did not significantly affect EGFR kinase activity. PPT significantly inhibited the cell viability of HCC827GR cells, whereas the PPT-treated HCC827 cells showed a cell viability of more than 80%. PPT dose-dependently induced G2/M cell cycle arrest, as shown by the downregulation of cyclin B1 and cdc2, and upregulation of p27 expression in HCC827GR cells. Furthermore, PPT treatment induced Bad expression and downregulation of Mcl-1, survivin, and Bcl-xl expression, subsequently activating multi-caspases. PPT thereby induced caspase-dependent apoptosis in HCC827GR cells. CONCLUSION: These results suggest the potential of PPT as a c-MET inhibitor to overcome tyrosine kinase inhibitor resistance in lung cancer.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Podofilotoxina/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/genética , Gefitinib/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Podofilotoxina/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo
15.
Chem Biol Interact ; 333: 109320, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33181113

RESUMEN

Betulinic acid and betulin show promising activity against cancers cells, but the mechanism of their action is still unclear. In this study, non-small cell lung cancer (NSCLC) cell lines: A549, H358 and NCI-H1703 were treated with betulinic acid and betulin under normoxic and hypoxic conditions as hypoxia is critically involved in the response of solid tumors to chemotherapy. The treatment inhibits viability and proliferation of NSCLC cells. The anti-proliferative effect was induced by G1 cell cycle arrest with increased p21 expression and decreased cyclin D1 and cyclin B1 expression. Additionally, downregulation of p-GSK3ß activity and the Wnt/ß-catenin pathway were also observed under hypoxia. We found that hypoxia increased apoptosis in NSCLC cells. Cell death was associated with changes in the expression of proteins involved in the mitochondrial apoptosis pathway and induction of apoptotic death by caspase activation. Additionally, hypoxia exposure deregulated HIF-1α and p53 expression levels. Importantly, treatment with betulinic acid and betulin reduced colony-forming ability under normoxia, however, only betulinic acid reduced clonogenic activity under hypoxia. Our findings that betulinic acid increases apoptotic cell death and clonogenic activity under hypoxic conditions reveal new attractive strategies for treating hypoxic cancer tumors, such as NSCLC.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Triterpenos Pentacíclicos/farmacología , Triterpenos/farmacología , Hipoxia Tumoral/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos
16.
Chem Biol Interact ; 333: 109330, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33245929

RESUMEN

AIM: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties. METHODS: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-ß (TGF-ß), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83+, CD8+ and CD166+ cell percentage were measured in lung tissue. RESULTS: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-ß, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83+ cells, CD8+ cells and increased number of CD166+ cells. CONCLUSION: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.


Asunto(s)
Benzo(a)pireno/farmacología , Carcinogénesis/efectos de los fármacos , Inmunosupresores/farmacología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Animales , Antígenos CD/metabolismo , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Femenino , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interleucina-12/genética , Ratones , Análisis de Supervivencia , Factor de Crecimiento Transformador beta/genética , Carga Tumoral/efectos de los fármacos
17.
Clin Nucl Med ; 46(1): e1-e2, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33156049

RESUMEN

A 51-year-old woman with newly diagnosed lung cancer experienced progressive left hip pain for 1 month. F-FDG PET/CT showed multiple hypermetabolic lesions throughout the body, including a suspicious lesion in the brain. Elevated FDG activity in select muscles was visualized, which was attributed to altered weight bearing. Unexpectedly, Ga-fibroblast activation protein inhibitor PET/CT showed the FDG-avid lesion in the brain with excellent imaging contrast. Brain metastasis was confirmed by a cerebral MRI.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Pulmonares/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Quinolinas/metabolismo , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad
18.
Nat Commun ; 11(1): 6119, 2020 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-33257678

RESUMEN

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Quimiocina CCL7/metabolismo , Quimiocina CCL7/farmacología , Inmunidad , Inmunoterapia/métodos , Neoplasias Pulmonares/inmunología , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimiocina CCL7/deficiencia , Quimiocina CCL7/genética , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Genes ras , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor
19.
Anticancer Res ; 40(12): 6835-6844, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33288575

RESUMEN

BACKGROUND/AIM: Adhesion G protein-coupled receptors (aGPCRs) have a crucial role in cancer. However, the role of ADGRF4, one of aGPCRs, in cancer has yet to be revealed. Therefore, we investigated its role in lung cancer, a leading cause of cancer-related deaths worldwide. MATERIALS AND METHODS: ADGRF4 gene expression pattern in lung cancer were analyzed by in silico analyses. RNA sequencing was conducted to investigate gene expression pattern altered by ADGRF4 knockdown. Lung cancer cell lines were subjected to cell migration and invasion assays. RESULTS: In silico analysis data indicated a major role of ADGRF4 in lung cancer. RNA sequencing data showed that ADGRF4 gene silencing in lung cancer cells altered global expression pattern. ADGRF4 gene silencing reduced lung cancer cell invasiveness. Furthermore, PPP2C gene expression was most significantly down-regulated by ADGRF4 gene silencing. PPP2C overexpression rescued cell invasiveness inhibited by ADGRF4 gene silencing, and PPP2C gene silencing blocked lung cancer cell invasiveness. CONCLUSION: ADGRF4 regulates lung cancer cell invasiveness via PPP2C.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores Acoplados a Proteínas G/genética , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/mortalidad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Receptores Acoplados a Proteínas G/metabolismo
20.
Medicine (Baltimore) ; 99(50): e21789, 2020 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-33327221

RESUMEN

X inactive specific transcript (XIST) is a novel long noncoding RNA (lncRNA) which has been reported to be frequently upregulated in various human cancer types and to function as an oncogene. It has been reported that the expression of lncRNA XIST was upregulated in non-small cell lung cancer (NSCLC). In the present study, we aimed to investigate the clinical significance and prognostic value of XIST in patients with NSCLC.A total of 156 pairs of NSCLC and corresponding adjacent normal lung tissue samples were obtained from NSCLC patients who had undergone surgery from July 2014 to March 2019. The Student's t test was used in different treated groups for statistical analysis. The association between XIST expression and clinicopathological features of NSCLC patients was evaluated using the chi-squared test. Survival curves were plotted using Kaplan-Meier method and compared by log-rank test.The expression of XIST was significantly higher in NSCLC samples compared to non-cancerous samples (P < .001). Statistically significant correlations were observed between high tissue XIST expression level and lymph node metastasis (P = .036) and high Tumor Node Metastasis (TNM) stage (P = .002). The log-rank test indicated that patients with increased XIST expression experienced poor overall survival (P = .006). Multivariate Cox regression analysis showed that XIST expression level (hazard ratio = 2.645, 95% confidence interval: 1.672-7.393, P = .029) was an independent factors in predicting the overall survival of NSCLC patients.The present study found that XIST expression level was significantly associated with advanced pathological stage and high TNM stage in NSCLC. Furthermore, upregulation of tissue lncRNA XIST predicts poor postoperative survival in patients with NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/patología , ARN Largo no Codificante/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , China/epidemiología , Femenino , Humanos , Metástasis Linfática/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Activación Transcripcional , Regulación hacia Arriba/genética
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