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1.
Int J Nanomedicine ; 17: 3287-3311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35924261

RESUMO

Purpose: The present study aimed to develop gefitinib-loaded solid lipid nanoparticles (GEF-SLN), and GEF-loaded PEGylated SLN (GEF-P-SLN) for targeting metastatic lung cancer through the lymphatic system. Methods: The prepared SLNs were characterized in terms of physicochemical properties, entrapment efficiency, and in-vitro release. Furthermore, ex-vivo permeability was investigated using the rabbit intestine. Cytotoxicity and apoptotic effects were studied against A549 cell lines as a model for lung cancer. Results: The present results revealed that the particle size and polydispersity index of the prepared formulations range from 114 to 310 nm and 0.066 to 0.350, respectively, with negative zeta-potential (-14 to -27.6). Additionally, SLN and P-SLN showed remarkable entrapment efficiency above 89% and exhibited sustained-release profiles. The permeability study showed that GEF-SLN and GEF-P-SLN enhanced the permeability of GEF by 1.71 and 2.64-fold, respectively, compared with GEF suspension. Cytotoxicity showed that IC50 of pure GEF was 3.5 µg/mL, which decreased to 1.95 and 1.8 µg/mL for GEF-SLN and GEF-P-SLN, respectively. Finally, the apoptotic study revealed that GEF-P-SLN decreased the number of living cells from 49.47 to 3.43 when compared with pure GEF. Conclusion: These results concluded that GEF-P-SLN is a promising approach to improving the therapeutic outcomes of GEF in the treatment of metastatic lung cancer.


Assuntos
Neoplasias Pulmonares , Nanopartículas , Animais , Portadores de Fármacos/química , Gefitinibe/uso terapêutico , Lipídeos/química , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Sistema Linfático , Nanopartículas/química , Tamanho da Partícula , Polietilenoglicóis/uso terapêutico , Coelhos
2.
Int J Biol Sci ; 18(9): 3636-3652, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813479

RESUMO

Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Antineoplásicos , Isoflavonas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Neoplasias Pulmonares/genética , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio
3.
Neurol India ; 70(3): 1197-1199, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35864664

RESUMO

Calcific miliary brain metastasis is an extremely rare form of brain secondaries. A 52-year-old man diagnosed with lung adenocarcinoma, on oncotherapy with gefitinib had a partial initial response to treatment. Later he was readmitted with seizures and cognitive dysfunction. His initial brain computed tomography (CT) and magnetic resonance imaging (MRI) were normal. However, his later CT images revealed multiple small calcified lesions over both hemispheres and contrast MRI revealed scattered tiny miliary nodules enhanced by gadolinium over bilateral cerebral, cerebellar hemispheres, thalami, and basal ganglia with foci of hypointensity in susceptibility-weighted images (SWI) and phase imaging suggesting calcification. A diagnosis of calcific miliary brain metastasis was made. Miliary calcification as an initial presentation of brain metastases in patients with lung cancer is uncommon. Use of oral tyrosine kinase inhibitor like gefitinib increases the likelihood development of calcific brain metastases due to the prolonged survival time contributed by its use.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Encefálicas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Gefitinibe/uso terapêutico , Humanos , Pulmão/patologia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade
4.
Int J Mol Sci ; 23(14)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35887373

RESUMO

Acquired drug resistance decreases the efficacy of gefitinib after approximately 1 year of treatment in non-small-cell lung cancer (NSCLC). Autophagy is a process that could lead to cell death when it is prolonged. Thus, we investigated a drug combination therapy of gefitinib with rapamycin-a cell autophagy activator-in gefitinib-resistant NSCLC cell line H1975 to improve the therapeutic efficacy of gefitinib in advanced NSCLC cells through acute cell autophagy induction. Cell viability and tumor formation assays indicated that rapamycin is strongly synergistic with gefitinib inhibition, both in vitro and in vivo. Mechanistic studies demonstrated that EGFR expression and cell autophagy decreased under gefitinib treatment and were restored after the drug combination therapy, indicating a potential cell autophagy-EGFR positive feedback regulation. To further optimize the delivery efficiency of the combinational agents, we constructed an anti-EGFR aptamer-functionalized nanoparticle (NP-Apt) carrier system. The microscopic observation and cell proliferation assays suggested that NP-Apt achieved remarkably targeted delivery and cytotoxicity in the cancer cells. Taken together, our results suggest that combining rapamycin and gefitinib can be an efficacious therapy to overcome gefitinib resistance in NSCLC, and targeted delivery of the drugs using the aptamer-nanoparticle carrier system further enhances the therapeutic efficacy of gefitinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Autofagia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico
5.
Cell Death Dis ; 13(7): 657, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902569

RESUMO

Gefitinib has been widely applied for the treatment of lung adenocarcinoma (LUAD). However, the long-term application of gefitinib usually leads to acquired drug resistance in tumour patients, resulting in clinical treatment failure. Small nucleolar host gene 17 (SNHG17) has been shown to play a regulatory role in LUAD progression. Nevertheless, the role of SNHG17 in LUAD gefitinib resistance remains elusive. The expression pattern of SNHG17 was examined in tissues and cell lines of gefitinib-sensitive and gefitinib-resistant LUAD, respectively. Gain- and loss-of-function experiments were employed to assess the biological functions of SNHG17 in cell proliferation and apoptosis, as well as aggressive phenotypes of LUAD cells. MeRIP-qPCR and colorimetric quantificational analysis were performed to detect m6A modifications and contents. Fluorescence in situ hybridisation (FISH) and subcellular fractionation analysis were used to reveal the distribution of SNHG17. RIP and ChIP assays were performed to further validate the SNHG17/EZH2/LATS2 regulatory axis. A xenograft tumour growth assay was conducted to evaluate the role of SNHG17 in LUAD gefitinib resistance in vivo. SNHG17 was upregulated in gefitinib-resistant LUAD tissues and cell lines. Functional assays showed that SNHG17 aggravated the malignant phenotypes of gefitinib-resistant LUAD cells. In addition, METTL3-mediated N6-methyladenosine modification could induce the upregulation of SNHG17by stabilising its RNA transcript. Mechanistically, SNHG17 epigenetically repressed the expression of LATS2 by recruiting EZH2 to the promoter region of LATS2. The regulatory role of the SNHG17/EZH2/LATS2 axis in LUAD gefitinib resistance was further supported in vivo. Collectively, our findings suggested that SNHG17 induced by METTL3 could promote LUAD gefitinib resistance by epigenetically repressing LATS2 expression.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Adenocarcinoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
Comput Biol Med ; 147: 105787, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35803080

RESUMO

Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), including L858R/T790M double and L858R/T790M/C797S triple mutations, are major causes of acquired resistance towards EGFR targeted drugs. In this work, a combination of comprehensive molecular modeling and in vitro kinase inhibition assay was used to unravel the mutational effects of EGFR on the susceptibility of three generations of EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) in comparison with the wild-type EGFR. The binding affinity of all studied inhibitors towards the double and triple EGFR mutations was in good agreement with the experimental data, ranked in the order of osimertinib > afatinib > dacomitinib > erlotinib > gefitinib. Three hot-spot residues at the hinge region (M790, M793, and C797) were involved in the binding of osimertinib and afatinib, enhancing their inhibitory activity towards mutated EGFRs. Both double and triple EGFR mutations causing erlotinib and gefitinib resistance are mainly caused by the low number of H-bond occupations, the low number of surrounding atoms, and the high number of water molecules accessible to the enzyme active site. According to principal component analysis, the molecular complexation of osimertinib against the two mutated EGFRs was in a closed conformation, whereas that against wild-type EGFR was in an open conformation, resulting in drug resistance. This work paves the way for further design of the novel EGFR inhibitors to overcome drug resistance mechanisms.


Assuntos
Receptores ErbB , Neoplasias Pulmonares , Afatinib/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
7.
Sci Adv ; 8(26): eabm7212, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35776787

RESUMO

In this study, we experimentally measure the frequency-dependent interactions between a gefitinib-resistant non-small cell lung cancer population and its sensitive ancestor via the evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion and that frequency-dependent growth rate measurements are required. Using frequency-dependent growth rate data, we then show that gefitinib treatment results in competitive exclusion of the ancestor, while the absence of treatment results in a likely, but not guaranteed, exclusion of the resistant strain. Then, using simulations, we demonstrate that incorporating ecological growth effects can influence the predicted extinction time. In addition, we show that higher drug concentrations may not lead to the optimal reduction in tumor burden. Together, these results highlight the potential importance of frequency-dependent growth rate data for understanding competing populations, both in the laboratory and as we translate adaptive therapy regimens to the clinic.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Evolução Biológica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico
8.
Int J Mol Sci ; 23(12)2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35743223

RESUMO

Accumulating evidence indicates that microRNAs (miRs) play critical roles in essentially all biological processes and their altered expression has been documented in various disease conditions, including human malignancies. Although several cellular mechanisms have been identified in mediating the effects of miRs, the involvement of G-protein-coupled, platelet-activating factor-receptor (PAFR) signaling in miR-149-5p-induced effects on lung cancer growth and therapeutic potential has not been studied. To that end, we first evaluated the functional significance of PAFR and miR-149-5p in A549 and H1299 human non-small cell lung cancer (NSCLC) cell lines. We observed that these tumor lines express endogenous PAFR and miR-149-5p and that PAFR activation by PAF agonist (CPAF) significantly increased, whereas miR-149-5p mimic transfection inhibited cell proliferation in a dose-dependent manner. Interestingly, miR-149-5p mimic significantly attenuated CPAF-mediated increased proliferation of NSCLC cells, as confirmed by miR-149-5p, cyclin D1, and forkhead box protein M1 (FOXM1) expression analysis via qPCR. Our next studies examined PAFR- and miR-149-5p-mediated effects on targeted therapy (i.e., erlotinib and gefitinib) responses. We observed that erlotinib and gefitinib inhibited A549 and H1299 cell survival in a dose- and time-dependent manner, and CPAF significantly blocked this effect. These findings indicate that miR-149-5p blocks PAFR-mediated increased cell proliferation, and PAFR activation attenuates the cytotoxic effects of targeted therapy.


Assuntos
Fenômenos Biológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo
9.
Future Oncol ; 18(21): 2695-2707, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35695676

RESUMO

Aim: To investigate the efficacy and safety of adjuvant EGFR tyrosine kinase inhibitors for resected EGFR-mutated non-small-cell lung cancer. Materials & methods: Eligible phase II/III randomized controlled trials were included for the network meta-analyses (PROSPERO CRD42021275150). Results: Nine records and 831 patients were involved. Adjuvant chemotherapy followed with osimertinib significantly prolonged disease-free survival compared with chemotherapy (hazard ratio [HR]: 0.2; 95% CI: 0.14-0.29), chemotherapy followed with erlotinib (HR: 0.33; 95% CI: 0.18-0.6), chemotherapy followed with gefitinib (HR: 0.36; 95% CI: 0.16-0.82), gefitinib (HR: 0.26; 95% CI: 0.17-0.41) and icotinib (HR: 0.56; 95% CI: 0.3-0.98). Icotinib was the least likely to cause grade ≥3 adverse events. Conclusion: Chemotherapy followed with osimertinib brings about the best disease-free survival. Icotinib monotherapy shows the best safety.


Patients with early-stage non-small-cell lung cancer have about a one in five chance of cancer recurrence, even after complete resection. Using agents targeting EGFR, known as adjuvant EGFR tyrosine kinase inhibitors, after surgery is an effective way for patients with EGFR-mutated non-small-cell lung cancer to prevent recurrence. However, the optimal agent with favorable efficacy and safety is yet to be determined. This study showed that adjuvant chemotherapy followed with osimertinib had the best efficacy, while adjuvant icotinib monotherapy had the best safety.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Metanálise em Rede , Inibidores de Proteínas Quinases/efeitos adversos
10.
Clin Lung Cancer ; 23(5): 410-418, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35649817

RESUMO

INTRODUCTION: Plasma cfDNA-based mutation analysis has shown disease-monitoring potential in various cancers. We assessed the potential of cfDNA-based EGFR mutation testing as a monitoring tool in patients with NSCLC. PATIENTS AND METHODS: Patients with NSCLC harboring EGFR mutations receiving first-line treatment as per institutional protocol were enrolled. EGFR mutation status was determined using plasma samples at baseline and post treatment initiation. Patients in whom EGFR mutation was detected or persisted after treatment initiation were considered circulating tumor DNA (ctDNA)-positive. Progression-free survival (PFS) and overall survival (OS) for ctDNA-positive and negative patients post treatment initiation were the primary endpoints; concordance for baseline EGFR status between tissue and plasma and proportion of patients who were ctDNA-positive post treatment initiation were the secondary endpoints. RESULTS: We enrolled 158 patients; 76 received gefitinib, and 82 received gefitinib plus chemotherapy. Median follow-up duration was 42 months. About 25% of patients were ctDNA-positive post treatment initiation. Median PFS for ctDNA-negative patients post treatment initiation was 14 (95% confidence interval [CI], 12.0-17.0) months, while that for ctDNA-positive patients was 8 (95% CI, 6.0-10.0) months. Median OS for ctDNA-negative patients post treatment initiation was 27 (95% CI, 24.0-32.0) months, while that for ctDNA-positive patients was 15 (95% CI, 11.0-19.0) months. Concordance at baseline between tissue and plasma samples was 75.4%. CONCLUSION: Plasma-based EGFR mutation detection post treatment initiation can be used as a predictive marker for outcome in patients with EGFR-mutant NSCLC receiving first-line treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Humanos , Biópsia Líquida , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico
11.
AAPS PharmSciTech ; 23(6): 183, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35773422

RESUMO

The present study aimed to engineer a nanoscale lipid-based lymphatic drug delivery system with D-α-Tocopherol polyethylene glycol 1000 succinate to combat the lymphatic metastasis of lung cancer. The nanoscale lipid-based systems including GEF-SLN, GEF-NLC, and GEF-LE were prepared and pharmaceutically characterized. In addition, the most stable formulation (GEF-NLC) was subjected to an in vitro release study. Afterward, the optimized GEF-NLC was engineered with TPGS (GEF-TPGS-NLC) and subjected to in vitro cytotoxicity, and apoptotic studies using the A549 cells line as a surrogate model for lung cancer. The present results revealed that particle size and polydispersity index of freshly prepared formulations were ranging from 198 to 280 nm and 0.106 to 0.240, respectively, with negative zeta potential ranging from - 14 to - 27.6.mV. An in vitro release study showed that sustained drug release was attained from GEF-NLC containing a high concentration of lipid. In addition, GEF-NLC and GEF-TPGS-NLC showed remarkable entrapment efficiency above 89% and exhibited sustained release profiles. Cytotoxicity showed that IC50 of pure GEF was 11.15 µg/ml which decreased to 7.05 µg/ml for GEF-TPGS-NLC. The apoptotic study revealed that GEF-TPGS-NLC significantly decreased the number of living cells from 67 to 58% when compared with pure GEF. The present results revealed that the nanoscale and lipid composition of the fabricated SLN, NLC, and LE could mediate the lymphatic uptake of GEF to combat the lymphatic tumor metastasis. Particularly, GEF-TPGS-NLC is a promising LDDS to increase the therapeutic outcomes of GEF during the treatment of metastatic lung cancer.


Assuntos
Neoplasias Pulmonares , Nanopartículas , Células A549 , Linhagem Celular Tumoral , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Gefitinibe , Humanos , Lipídeos , Neoplasias Pulmonares/tratamento farmacológico , Tamanho da Partícula , Vitamina E
12.
Molecules ; 27(12)2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35744964

RESUMO

Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed understanding of the molecular basis for multiple EGFR mutants exhibiting diverse responses to inhibitors is of critical importance for related drug development. Herein, we explored the molecular determinants contributing to the distinct responses of EGFR with a single rare mutation (G719S) or combined mutations (G719S/L858R and G719S/l861Q) to Gefitinib (IRE). Our results indicated that interactions, formed within the tetrad of residues S768 (in the αC-helix), D770 (in the αC-ß4 loop), Y827 (in the αE-helix), and R831 (in the catalytic loop), play an important role in the stability of αC-helix and the maintenance of K745-E762 salt bridge in the absence of IRE, which are weakened in the EGFRG719S system and enhanced in the EGFRG719S/L858R system upon IRE binding. Besides, the introduced hydrogen bonds by the co-occurring mutation partner also contribute to the stability of αC-helix. The work done for inhibitor dissociation suggests that IRE exhibits a stronger binding affinity to EGFRG719S/L858R mutant. Together, these findings provide a deeper understanding of minor mutations, which is essential for drug development targeting EGFR with less common mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/química , Quinazolinas/farmacologia
13.
Thorac Cancer ; 13(14): 2057-2063, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35668712

RESUMO

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line treatment in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR-TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first-line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation. METHODS: A retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first-line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression-free survival (PFS) with first-line EGFR-TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first-line EGFR-TKIs. RESULTS: Among 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first-line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first-line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance. CONCLUSIONS: First-line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR-TKI in the first-line setting.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Afatinib/farmacologia , Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
14.
Biomed Res Int ; 2022: 4541918, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35496045

RESUMO

To study the mechanism of circular ribonucleic acid (RNA) circHIPK3 involved in the resistance of lung cancer cells to gefitinib, 110 patients with lung cancer were recruited as the research objects, and the tumor tissue and para-cancerous tissue of each patient's surgical specimens were collected and paraffinized to detect the expression of circHIPK3 in different tissues. Gefitinib drug-resistant cell line of lung cancer was constructed with gefitinib to detect cell apoptosis under different conditions. As a result, the relative expression of circHIPK3 in patients with tumor diameter no less than 3 cm was dramatically inferior to that in patients with tumor diameter less than 3 cm (P < 0.05). The relative expression of circHIPK3 in patients with TNM stage II/III was dramatically inferior to that in patients with tumor, node, and metastasis (TNM) stage I (P < 0.05). Expression of circHIPK3 in patients with lymph node metastasis was dramatically inferior to that in patients without lymph node metastasis (P < 0.05). Of the lung cancer tissues of patients with different TNM stages, only six patients had high expression, and the remaining 104 patients had low expression. Moreover, electrophoresis revealed that circHIPK3 can only be amplified in cDNA, but not in gDNA. Gefitinib-mediated apoptosis rate of lung cancer drug-resistant cell lines decreased notably. In summary, the circular RNA circHIPK3 may have a notably low expression in lung cancer tissues, whose low expression had a certain enhancement effect on the drug resistance of lung adenocarcinoma cells to gefitinib.


Assuntos
Neoplasias Pulmonares , MicroRNAs , Linhagem Celular Tumoral , Proliferação de Células/genética , Gefitinibe/farmacologia , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Linfática , MicroRNAs/genética , RNA Circular/genética
15.
Free Radic Res ; 56(2): 196-208, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35514158

RESUMO

Erlotinib and gefitinib are quinazoline derivatives with antineoplastic properties. Usually, intake of antineoplastic agents results in much a greater degree of oxidative stress, i.e. the production of free radicals, than induced by cancer itself. Hence, anticancerous drugs must also exhibit antioxidant activity but this has not been studied thus far. In this study, the antioxidant activity of erlotinib and gefitinib was examined by experimental and computational studies. It was found that erlotinib and gefitinib exhibit good 2,2-dipheny l-1-picrylhydrazyl (DPPH) radical and hydroxyl radical scavenging (HRS) activities. In DPPH assay, the IC50 for erlotinib and gefitinib were 0.584 and 0.696 mM, respectively, while IC50 for HRS assay were 0.843 and 1.03 mM for erlotinib and gefitinib, respectively. Structural characteristics such as frontier molecular orbitals (FMOs), molecular electrostatic potential maps (MESPs), and global descriptive parameters were calculated at DFT/B3LYP/6-311++G (d,p) on the optimized geometries of erlotinib and gefitinib. UV-visible spectroscopy revealed the possible electronic transitions between the FMOs and their associated excitation energies of both drugs and found that erlotinib has π to π* transitions while gefitinib has π to π* and σ to π* transitions. To elucidate the antioxidant activity of erlotinib and gefitinib, three mechanisms namely hydrogen atom transfer (HAT), single electron transfer proton transfer (SETPT), and sequential proton-loss electron-transfer (SPLET) were employed and articulated the results in arithmetic parameters like bond dissociation energy (BDE), proton affinity (PA), ionization potential (IP), electron transfer enthalpy (ETE), and proton dissociation enthalpy (PDE). Further, molecular docking studies have been carried out to have a better understanding of binding sites and modes of interaction with a well-known antioxidant target protein monoamine oxidase-B (MAO-B) employing docking scores and types of interactions. All the calculated parameters point out that though gefitinib and erlotinib were interchangeable, erlotinib requires a lesser amount of energy for proton transfer and electron transfer, moreover it scavenges radicals easily.


Assuntos
Antioxidantes , Prótons , Antioxidantes/química , Antioxidantes/farmacologia , Cloridrato de Erlotinib/farmacologia , Gefitinibe , Simulação de Acoplamento Molecular , Termodinâmica
16.
Signal Transduct Target Ther ; 7(1): 157, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35551173

RESUMO

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.


Assuntos
Fibrose Pulmonar , Silicose , Aminopiridinas , Animais , Receptores ErbB , Gefitinibe/farmacologia , Inflamação , Camundongos , Morfolinas , Fibrose Pulmonar/patologia , Piridinas/uso terapêutico , Pirimidinas , Silicose/tratamento farmacológico , Silicose/genética , Silicose/metabolismo
17.
Thorac Cancer ; 13(12): 1827-1836, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35562327

RESUMO

BACKGROUND: Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC. METHODS: Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. RESULTS: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). CONCLUSIONS: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Docetaxel/uso terapêutico , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Pemetrexede/uso terapêutico
18.
Oncogene ; 41(22): 3104-3117, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35468939

RESUMO

Kelch superfamily involves a variety of proteins containing multiple kelch motif and is well characterized as substrate adaptors for CUL3 E3 ligases, which play critical roles in carcinogenesis. However, the role of kelch proteins in lung cancer remains largely unknown. In this study, the non-small cell lung cancer (NSCLC) patients with higher expression of a kelch protein, kelch domain containing 3 (KLHDC3), showed worse overall survival. KLHDC3 deficiency affected NSCLC cell lines proliferation in vitro and in vivo. Further study indicated that KLHDC3 mediated CUL2 E3 ligase and tumor suppressor p14ARF interaction, facilitating the N-terminal ubiquitylation and subsequent degradation of p14ARF. Interestingly, Gefitinib-resistant NSCLC cell lines displayed higher KLHDC3 protein levels. Gefitinib and Osimertinib medications were capable of upregulating KLHDC3 expression to promote p14ARF degradation in the NSCLC cell lines. KLHDC3 shortage significantly increased the sensitivity of lung cancer cells to epidermal growth factor receptor (EGFR)-targeted drugs, providing an alternative explanation for the development of Gefitinib and Osimertinib resistance in NSCLC therapy. Our works suggest that CRL2KLHDC3 could be a valuable target to regulate the abundance of p14ARF and postpone the occurrence of EGFR-targeted drugs resistance.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Repetição Kelch , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteína Supressora de Tumor p14ARF/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
19.
Drug Resist Updat ; 62: 100832, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35427871

RESUMO

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistência a Medicamentos , Gefitinibe/uso terapêutico , Células Germinativas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
20.
Oxid Med Cell Longev ; 2022: 4750671, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432717

RESUMO

Epithelial membrane protein (EMP1), a member of the peripheral myelin protein (PMP22) family, is involved in the development of various human malignancies. However, the expression level of EMP1 and its functional role in head and neck squamous cell carcinoma (HNSCC) remain unclear to date. Ferroptosis, a newly characterized form of regulated cell death, plays an essential role in tumorigenesis. In this study, we aimed to investigate the expression levels of EMP1 in HNSCC and normal tissues, as well as to identify the function of EMP1 in regulating ferroptosis during the progression of HNSCC. To further explore the biological function of EMP1 in vitro, transient transfection was used to overexpress EMP1 in the HNSCC cell lines Hep2 and Detroit562. Functionally, our results indicated that EMP1 overexpression could not affect the initiation of ferroptosis directly but reinforced RSL3-induced ferroptosis on HNSCC cells. Furthermore, mechanical study indicated that EMP1 mediated the ferroptosis via cell density-regulated Hippo-TAZ pathway and regulated the expression of Rac1 and NOX1. In addition, our study demonstrated that EMP1 overexpression could promote gefitinib resistance by targeting the MAPK pathway. In summary, our findings indicate that EMP1 may act as an oncogene and serve as a therapeutic target against malignant progression of HNSCC.


Assuntos
Ferroptose , Neoplasias de Cabeça e Pescoço , Linhagem Celular Tumoral , Gefitinibe , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Proteínas de Neoplasias , Receptores de Superfície Celular , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
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