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1.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802212

RESUMEN

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v/v) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Dimetilsulfóxido/farmacología , Sistemas de Liberación de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biosíntesis , Transducción de Señal/efectos de los fármacos , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología
2.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807876

RESUMEN

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal-epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo
3.
Anticancer Res ; 41(4): 2093-2100, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813419

RESUMEN

BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.


Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antihipertensivos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Sinergismo Farmacológico , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Japón/epidemiología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Nivolumab/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
4.
Anticancer Res ; 41(4): 2165-2169, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813428

RESUMEN

BACKGROUND/AIM: In centrally-located lung cancer treatment, it is difficult to attain a sufficient resection margin. It is important to investigate recurrent styles in centrally-located lung cancer patients. PATIENTS AND METHODS: Primary lung cancer located at the hilar area that requires pneumonectomy or sleeve lobectomy is defined as centrally-located lung cancer. Early recurrence was defined as that within 1 year after surgery. RESULTS: This study included 43 centrally-located lung cancer patients. Ten patients underwent pneumonectomy and 33 underwent sleeve lobectomy. Eleven patients experienced early recurrence. Non-squamous cell carcinoma (p=0.012), tumor size>64 mm (p<0.001) and pathological N2 (p=0.012) were significant predictors for early recurrence by univariate analysis. Also, tumor size >64 mm (p=0.006) and pathological N2 (p=0.019) were independent predictors by multivariate analysis. CONCLUSION: Non-squamous cell carcinoma, tumor size and pathological N2 were significant predictors of early recurrence in centrally-located lung cancer. The type of surgical procedure did not affect recurrence development.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Ganglios Linfáticos/patología , Carga Tumoral/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neumonectomía/efectos adversos , Neumonectomía/métodos , Periodo Posoperatorio , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo
5.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799364

RESUMEN

Epithelial membrane proteins (EMP1-3) are involved in epithelial differentiation and carcinogenesis. Dysregulated expression of EMP2 was observed in various cancers, but its role in human lung cancer is not yet clarified. In this study, we analyzed the expression of EMP1-3 and investigated the biological function of EMP2 in non-small cell lung cancer (NSCLC). The results showed that lower expression of EMP1 was significantly correlated with tumor size in primary lung tumors (p = 0.004). Overexpression of EMP2 suppressed tumor cell growth, migration, and invasion, resulting in a G1 cell cycle arrest, with knockdown of EMP2 leading to enhanced cell migration, related to MAPK pathway alterations and disruption of cell cycle regulatory genes. Exosomes isolated from transfected cells were taken up by tumor cells, carrying EMP2-downregulated microRNAs (miRNAs) which participated in regulation of the tumor microenvironment. Our data suggest that decreased EMP1 expression is significantly related to increased tumor size in NSCLC. EMP2 suppresses NSCLC cell growth mainly by inhibiting the MAPK pathway. EMP2 might further affect the tumor microenvironment by regulating tumor microenvironment-associated miRNAs.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/genética , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Receptores de Superficie Celular/genética , Microambiente Tumoral/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Exosomas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Transducción de Señal/genética
6.
Anticancer Res ; 41(4): 2053-2058, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813413

RESUMEN

AIM: To investigate potential associations between selected oncomarkers [carcinoembryonic antigen (CEA), C-terminus of cytokeratin 19 (CYFRA 21-1, CYFRA), and squamous cell carcinoma antigen (SCC)] and outcomes in patients with NSCLC treated with bevacizumab plus chemotherapy. PATIENTS AND METHODS: We retrospectively analysed 105 patients with NSCLC from the Czech TULUNG registry treated at University Hospital in Pilsen with bevacizumab plus chemotherapy. Response to therapy was tested by Fisher's exact test. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. RESULTS: Only normal values of CYFRA (not CEA or SCC) were associated with significantly better overall and progression-free survival in univariate analysis. We also observed a trend for a better disease control rate in patients with normal levels of CYFRA. In a multivariate Cox model, only CYFRA was associated with significantly better overall but not progression-free survival. CONCLUSION: In our retrospective study, we point out the possibility of using CYFRA as a prognostic marker in patients with NSCLC treated with chemotherapy plus bevacizumab.


Asunto(s)
Antígenos de Neoplasias/fisiología , Antineoplásicos/uso terapéutico , Bevacizumab/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Queratina-19/fisiología , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/sangre , Bevacizumab/efectos adversos , Biomarcadores Farmacológicos/análisis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/fisiología , Antígeno Carcinoembrionario/análisis , Antígeno Carcinoembrionario/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Humanos , Queratina-19/análisis , Queratina-19/sangre , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Serpinas/análisis , Serpinas/sangre , Resultado del Tratamiento
7.
Anticancer Res ; 41(4): 2059-2065, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813414

RESUMEN

BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.


Asunto(s)
Afatinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , República Checa/epidemiología , Progresión de la Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
8.
Int J Nanomedicine ; 16: 2357-2372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790554

RESUMEN

Purpose: Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality and poor prognosis. In this study, we designed a liposome encapsulating polymeric micelles (PMs) loaded with vinorelbine (NVB) and cis-diamminedichloroplatinum (II) (cisplatin or CDDP) for the treatment of NSCLC. Materials and Methods: Sodium poly(α-l-glutamic acid)-graft-methoxy-polyethylene glycol (PLG-G-PEG5K) was used to prepare NVB-loaded NVB-PMs and CDDP-loaded CDDP-PMs that were co-encapsulated into liposomes by a reverse evaporation method, yielding NVB and CDDP co-delivery liposomes (CoNP-lips) composed of egg phosphatidyl lipid-80/cholesterol/DPPG/DSPE-mPEG2000 at a molar ratio of 52:32:14:2. The CoNP-lips were characterized in terms of particle size, zeta potential, drug content, encapsulation efficiency, and structural properties. Drug release by the CoNP-lips as well as their stability and cytotoxicity was evaluated in vitro, and their antitumor efficacy was assessed in a mouse xenograft model of Lewis lung carcinoma cell-derived tumors. Results: CoNP-lips had a spherical shape with uniform size distribution; the average particle size was 162.97±9.06 nm, and the average zeta potential was -13.02±0.22 mV. In vitro cytotoxicity analysis and the combination index demonstrated that the CoNP-lips achieved a synergistic cytotoxic effect at an NVB:CDDP weight ratio of 2:1 in an NSCLC cell line. There was sustained release of both drugs from CoNP-lips. The pharmacokinetic analysis showed that CoNP-lips had a higher plasma half-life than NP solution, with 6.52- and 8.03-fold larger areas under the receiver operating characteristic curves of NVB and CDDP. CoNP-lips showed antitumor efficacy in tumor-bearing C57BL/6 mice and drug accumulation in tumors via the enhanced permeability and retention effect. Conclusion: CoNP-lips are a promising formulation for targeted therapy in NSCLC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Micelas , Polímeros/química , Vinorelbina/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Cisplatino/farmacología , Liberación de Fármacos , Humanos , Liposomas , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Tamaño de la Partícula , Polietilenglicoles/química , Ratas Sprague-Dawley , Distribución Tisular , Vinorelbina/farmacocinética , Vinorelbina/farmacología
9.
Medicine (Baltimore) ; 100(14): e24982, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832072

RESUMEN

RATIONALE: Hypercalcemia is a common finding in patients with advanced-stage cancers. Paraneoplastic hypercalcemia is commonly associated with dismal prognoses, with survival rates of about 3 months. In this paper, we report on a patient with advanced chronic lymphocytic leukemia and non-small cell lung carcinoma who developed severe hypercalcemia and discuss the diagnosis and treatment of this metabolic complication. PATIENT CONCERNS: A 56-year old male with a 2-year history of Rai stage IV chronic lymphocytic leukemia presented with life-threatening hypercalcemia. Positron emission tomography/computed tomography revealed a suspicious lung lesion. A transbronchial biopsy was performed from the upper left lobe. Due to the small size of the specimen, immunohistochemical markers were performed and revealed positive staining for cytokeratin 7 and negative for TTF-1, napsin A and p 40, which were consistent with non-small cell lung carcinoma. DIAGNOSIS: Humoral hypercalcemia of malignancy was diagnosed. INTERVENTION: The patient was treated with saline infusion, calcitonin, intravenous pamidronate, followed with denosumab. OUTCOMES: The hypercalcemia was successfully treated and the patient's calcium levels returned to normal. Further evaluation revealed a non-small cell lung carcinoma as a second primary malignancy. The patient was treated with venetoclax for his refractory CLL and received chemotherapy and immunotherapy for lung adenocarcinoma. Several days after starting venetoclax, he developed Legionella pneumonia and short time after the second course of chemotherapy, a severe sepsis occurred and he passed away. LESSONS: Coexistence of 2 unrelated malignancies, whichever could be a reason for hypercalcemia of malignancy is a rare event. Severe hypercalcemia, which is possible but rare feature of CLL should be a reason for further prompt evaluation.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inducido químicamente , Hipercalcemia/etiología , Leucemia Linfocítica Crónica de Células B/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Resultado Fatal , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones
10.
Anticancer Res ; 41(4): 1871-1882, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813392

RESUMEN

BACKGROUND: This study aimed to identify differentially expressed proteins in the serum of advanced non-small cell lung cancer (NSCLC) patients responding to carboplatin (CAR) plus paclitaxel (PTX) chemotherapy compared to non-responders. MATERIALS AND METHODS: Serum from 8 responders and 6 non-responders was subjected to proteomic analysis by label-free liquid chromatography tandem mass spectrometry and validated by western blotting. CAR/PTX-resistant human H1792 and A549 cells were used for evaluating gene expression. RESULTS: Fifty-two proteins were differentially expressed between responders and non-responders. Alpha 1 antitrypsin antibody, alpha 1 acid glycoprotein (A1AG1), afamin, protein S100-A9 and immunoglobulin heavy constant gamma 3 (IGHG3) were validated. IGHG3 was elevated (p=0.037) while A1AG1 was reduced (p=0.003) in responders as compared to non-responders. Gene expression of IGHG3 and ORM1 in resistant cells showed consistent results with the proteomics profiles. CONCLUSION: Serum expression levels of IGHG3 and A1AG1 proteins may be useful to recruit an NSCLC subpopulation that can benefit from CAR plus PTX standard therapy.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/sangre , Orosomucoide/análisis , Proteómica , Células A549 , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Toma de Decisiones Clínicas , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Valor Predictivo de las Pruebas , Resultado del Tratamiento
11.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670495

RESUMEN

Mercury is one of the detrimental toxicants that can be found in the environment and exists naturally in different forms; inorganic and organic. Human exposure to inorganic mercury, such as mercury chloride, occurs through air pollution, absorption of food or water, and personal care products. This study aimed to investigate the effect of HgCl2 on cell viability, cell cycle, apoptotic pathway, and alters of the transcriptome profiles in human non-small cell lung cancer cells, H1299. Our data show that HgCl2 treatment causes inhibition of cell growth via cell cycle arrest at G0/G1- and S-phase. In addition, HgCl2 induces apoptotic cell death through the caspase-3-independent pathway. Comprehensive transcriptome analysis using RNA-seq indicated that cellular nitrogen compound metabolic process, cellular metabolism, and translation for biological processes-related gene sets were significantly up- and downregulated by HgCl2 treatment. Interestingly, comparative gene expression patterns by RNA-seq indicated that mitochondrial ribosomal proteins were markedly altered by low-dose of HgCl2 treatment. Altogether, these data show that HgCl2 induces apoptotic cell death through the dysfunction of mitochondria.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Caspasa 3/genética , Perfilación de la Expresión Génica/métodos , Neoplasias Pulmonares/genética , Cloruro de Mercurio/farmacología , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
12.
Eur J Med Chem ; 216: 113312, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667849

RESUMEN

Among the lung cancers, approximately 85% are histologically classified as non-small-cell lung cancer (NSCLC), a leading cause of cancer deaths worldwide. Epidermal growth factor receptors (EGFRs) are known to play a crucial role in lung cancer. HER2 overexpression is detected by immunohistochemistry in 2.4%-38% of NSCLC samples. EGFRs have been targeted with three generations of tyrosine kinase inhibitors (TKIs), and drug resistance has become a major issue; HER2 dimerization with EGFR also plays a major role in the development of resistance to TKI therapy. We have designed grafted peptides to bind to the HER2 extracellular domain (ECD) and inhibit protein-protein interactions of EGFR:HER2 and HER2:HER3. A sunflower trypsin inhibitor (SFTI-1) template was used to graft a peptidomimetic compound. Among several grafted peptides, SFTI-G5 exhibited antiproliferative activity in HER2-positive NSCLC cell lines such as Calu-3 cells with an IC50 value of 0.073 µM. SFTI-G5 was shown to bind to ECD of HER2 and inhibit EGFR:HER2 and HER2:HER3 dimerization and inhibit the phosphorylation of HER2 and downstream signaling proteins. As a proof-of-concept, the in vivo activity of SFTI-G5 was evaluated in two NSCLC mouse models. SFTI-G5 was able to inhibit tumor growth in both models. Furthermore, SFTI-G5 was shown to inhibit EGFR dimerization in tissue samples obtained from in vivo models. These grafted peptides can be used as novel dual inhibitors of EGFR dimerization in NSCLC.


Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Peptidomiméticos/química , Inhibidores de Proteínas Quinasas/química , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dimerización , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Péptidos/química , Péptidos/metabolismo , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacología , Peptidomiméticos/uso terapéutico , Fosforilación/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante Heterólogo
13.
Medicine (Baltimore) ; 100(10): e25046, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725888

RESUMEN

RATIONALE: Genotypic and histological evolution of non-small-cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, the number of clinical cases is rare. PATIENT CONCERNS: Two lung adenocarcinoma patients with EGFR mutations who recurred after radical resection transformed into SCLC under treatment with the sequential first- and third-generation EGFR-TKIs. DIAGNOSIS: The 2 cases were both confirmed as SCLC by pathological rebiopsy after EGFR-TKIs resistance. INTERVENTIONS: Case 1 was treated with etoposide plus cisplatin (EP) regimen and erlotinib, while case 2 was treated with erlotinib and EP followed by oral etoposide. OUTCOMES: Case 1 treated with EP only achieved 3-month progression-free survival (PFS), which is the first case that reported T790 M/C797S cis-mutation for osimertinib resistance before the SCLC transformation. However, case 2 treated with erlotinib and EP followed by oral etoposide, PFS lasted for 8 months. LESSONS: The cases highlighted the importance of rebiopsy that identified pathologically SCLC transformation after EGFR-TKI resistance, and suggested the treatment of erlotinib plus EP followed by etoposide, which could provide a reference for such phenotype.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Pulmonar de Células Pequeñas/terapia , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adulto , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Epirrubicina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Resultado Fatal , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neumonectomía , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
14.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670440

RESUMEN

Cancer stem cells (CSCs) represent a small subpopulation within a tumour. These cells possess stem cell-like properties but also initiate resistance to cytotoxic agents, which contributes to cancer relapse. Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin. This study was designed to investigate the efficacy of curcumin as a chemo-sensitiser in CSCs subpopulation of non-small cell lung cancer (NSCLC) using the lung cancer adenocarcinoma human alveolar basal epithelial cells A549 and H2170. The ability of curcumin to sensitise lung CSCs to cisplatin was determined by evaluating stemness characteristics, including proliferation activity, colony formation, and spheroid formation of cells treated with curcumin alone, cisplatin alone, or the combination of both at 24, 48, and 72 h. The mRNA level of genes involved in stemness was analysed using quantitative real-time polymerase chain reaction. Liquid chromatography-mass spectrometry was used to evaluate the effect of curcumin on the CSC niche. A combined treatment of A549 subpopulations with curcumin reduced cellular proliferation activity at all time points. Curcumin significantly (p < 0.001) suppressed colonies formation by 50% and shrank the spheroids in CSC subpopulations, indicating inhibition of their self-renewal capability. This effect also was manifested by the down-regulation of SOX2, NANOG, and KLF4. Curcumin also regulated the niche of CSCs by inhibiting chemoresistance proteins, aldehyde dehydrogenase, metastasis, angiogenesis, and proliferation of cancer-related proteins. These results show the potential of using curcumin as a therapeutic approach for targeting CSC subpopulations in non-small cell lung cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/farmacología , Curcumina/farmacología , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Cisplatino/uso terapéutico , Curcumina/uso terapéutico , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo
15.
Anticancer Res ; 41(3): 1621-1628, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788758

RESUMEN

BACKGROUND/AIM: Albumin-bilirubin (ALBI) grade is an indicator of liver dysfunction and is useful for predicting postoperative prognosis of hepatocellular carcinomas. However, the significance of ALBI grade in non-small cell lung carcinoma (NSCLC) has not been elucidated. PATIENTS AND METHODS: We analyzed 947 patients with pStage IA-IIIA NSCLC. We divided patients into ALBI grade 1 and grade 2/3 groups. We then analyzed the association of ABLI grade with clinicopathological characteristics and prognosis in NSCLC by using propensity-score matching. RESULTS: ALBI grade 2/3 was significantly associated with older age, male sex, advanced pT status, and histological type. Even after propensity-score matching, ALBI grade 2/3 patients had significantly worse cancer-specific survival (CSS) than ALBI grade 1 patients (5-year CSS: 87.3% versus 92.8%; p=0.0247). In multivariate analysis, ALBI grade 2/3 was an independent predictor of CSS (HR=1.9; 95%CI=1.11-3.11; p=0.0177). CONCLUSION: ALBI grade was an independent prognostic factor in surgically resected NSCLC.


Asunto(s)
Bilirrubina/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/mortalidad , Puntaje de Propensión , Albúmina Sérica/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico
16.
Anticancer Res ; 41(3): 1693-1699, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788767

RESUMEN

AIM: To report two cases in which treatment with pembrolizumab for advanced non-small cell lung cancer (NSCLC) with bone metastasis of the long bone of the lower extremity in a state of impending fracture significantly ameliorated both lung tumor and bone metastasis. CASE REPORT: Case 1 was a 74-year-old woman diagnosed with metastasis of NSCLC in the left tibia and case 2 was a 71-year-old man diagnosed with metastasis of NSCLC in the right femur; their bone metastases were in a state of impending fracture. Disease in both cases was already in stage IVB and they received systemic therapy using pembrolizumab, whilst the bone metastases were treated conservatively. After 3 months, both patients showed a complete response with remarkable osteosclerotic changes in bone metastases and the size of lung tumors was reduced. CONCLUSION: These results might imply a novel strategy for systemic treatment with pembrolizumab is required, even in case of impending fracture in advanced NSCLC.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Anciano , Neoplasias Óseas/diagnóstico por imagen , Femenino , Humanos , Masculino
17.
Clinics (Sao Paulo) ; 76: e2251, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33787673

RESUMEN

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos
18.
Methods Mol Biol ; 2279: 59-73, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33683686

RESUMEN

In an era of precision medicine important treatment decisions are dictated by expression of clinically informative tumor protein biomarkers. These biomarkers can be detected by immunohistochemistry (IHC) performed in tumor tissue sections obtained from biopsies or resections. Like all experimental procedures, IHC needs optimization for several of its steps. However, the investigator must avoid optimizing the IHC procedure using valuable human biopsy samples which may be difficult to obtain. Ideally, valuable biopsy samples should only be subjected to IHC once the IHC protocol has been optimized. In this chapter, we describe a procedure for IHC optimization using tri-dimensional (3D) cellular spheroids created from cultured cells. In this approach, cultured cells are pelleted into 3D spheroids, which are then processed just like a tissue sample, namely, fixed, embedded, sectioned, mounted on slides, and stained with IHC just like a human tissue sample. These 3D cellular spheroids have a tissue-like architecture and cellularity resembling a tumor section, and both cellular and antigen structure are preserved. This method is therefore acceptable for IHC optimization before proceeding to the IHC staining of human tumor samples.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunohistoquímica , Neoplasias Pulmonares , Adhesión en Parafina , Esferoides Celulares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Formaldehído/química , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología
19.
Medicine (Baltimore) ; 100(11): e24987, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725970

RESUMEN

RATIONALE: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of non-small cell lung cancer (NSCLC). It is predominantly reported in East Asia and currently there is no standard treatment for this disease. We report a case of stage IV PPLELC that achieved pathological complete response (pCR) by neoadjuvant treatment. PATIENT CONCERNS: The patient was a 46-year-old male who developed hemoptysis for about 20 ml of volume accompanied by cough and sputum after physical labor. DIAGNOSES: Contrast enhanced chest CT scanning showed occupation of left lower hilar area and left pleural effusion. Combined with medical history and auxiliary examination, the patient was formally diagnosed stage IV lymphoepithelioma-like carcinoma of the left lower lung (T3N0M1a pleura). INTERVENTIONS: The patient was given Sintilimab combined with gemcitabine + nedaplatin chemotherapy (GP) regimen for four cycles with 3 weeks as a cycle, supplemented with antiemetics and stomach protection drugs to reduce chemotherapy-related side effects. OUTCOMES: After 4 cycles of treatment, the patient's left lung lesion has been markedly reduced and the left pleural effusion has also been significantly absorbed. Remarkably, surgical biopsies found no cancer cells in the lesion site and postoperative pathology showed complete pathological remission (pCR). LESSONS: We reported a case of PPLELC that is sensitive to neoadjuvant treatment, showing excellent effectiveness and safety and achieving pCR.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Terapia Neoadyuvante/métodos , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Pulmón/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pleura/patología , Derrame Pleural/etiología , Resultado del Tratamiento
20.
Cancer Treat Rev ; 95: 102173, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33740553

RESUMEN

The mesenchymal-epithelial transition (MET) receptor tyrosine kinase binds the hepatocyte growth factor to activate downstream cell signaling pathways involved in cell proliferation, survival, and migration. Several genetic mechanisms can result in an aberrant activation of this receptor in cancer cells. One such activating mechanism involves the acquisition of gene mutations that cause MET exon 14 skipping (METex14) during mRNA splicing. Mutations leading to METex14 are found in approximately 3-4% of patients with non-small cell lung cancer (NSCLC). Accumulating evidence suggests that METex14 is a true, independent oncogenic driver in NSCLC, as well as being an independent prognostic factor for poorer survival in patients with NSCLC. The successes of target therapies have relied on improved understanding of the genetic alterations that lead to the dysregulation of the molecular pathways and more advanced molecular diagnostics. Multiple efforts have been made to target the MET pathway in cancer; however, real clinical progress has only occurred since the emergence of METex14 as a valid biomarker for MET inhibition. Capmatinib is a highly potent and selective type Ib inhibitor of MET. Following preclinical demonstration of activity against MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models, data from a phase 1 clinical trial showed an acceptable safety profile of capmatinib and preliminary evidence of efficacy in patients with MET-dysregulated NSCLC. The multicohort GEOMETRY mono-1 phase 2 trial reported objective response rates of 68% and 41% in treatment-naïve and in pre-treated patients with METex14 advanced NSCLC, respectively. These results have supported the approval of capmatinib by the US Food and Drug Administration for patients with metastatic NSCLC harboring METex14.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Exones , Imidazoles/uso terapéutico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Triazinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología
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