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1.
AAPS PharmSciTech ; 23(1): 48, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34984564

RESUMO

Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.


Assuntos
Secagem por Atomização , Células CACO-2 , Liberação Controlada de Fármacos , Gefitinibe , Humanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Anticancer Res ; 42(1): 441-447, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969754

RESUMO

BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) gene have been utilized to predict the effectiveness of EGFR tyrosine kinase inhibitor (TKI) therapy. The most common EGFR mutations are exon 19 deletion and exon 21-point mutation, which are sensitive to EGFR TKI. However, rare/complex EGFR mutations still exist, data of which are scarce and controversial. Hence, their role in response to standard therapy remains uncertain. CASE REPORT: We present the case of a patient diagnosed with stage IV lung adenocarcinoma for whom standard chemotherapies, including platinum agents, had failed. The patient was found to have an EGFR exon 19 (L747P) mutation, as evident in her liquid biopsy. This alteration has not been described before in the literature on non-Asian females. Data from the current case study highlight the aggressive nature of this type of EGFR mutation as indicated by the complete resistance to erlotinib. Using standard first-generation EGFR inhibitors in treating this point mutation was considered inadequate. However, this patient showed a substantial response when treated with erlotinib combined with epigenetic therapies, consisting of DNA methyltransferase and histone deacetylase inhibitors. For more than 8 years, the patient has been responding to combination therapy with a normal quality of life. CONCLUSION: This case represents a possible novel approach to reducing resistance in patients harboring this rare EGFR mutation which may translate to better outcomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/administração & dosagem , Gefitinibe/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Epigênese Genética/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação/genética , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de Vida
3.
Kyobu Geka ; 74(12): 1039-1042, 2021 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-34795150

RESUMO

We present a case of a 54-year-old woman who had been performed video-assisted thoracic surgery (VATS) right upper lobectomy for stageⅡB adenocarcinoma. The patient had the recurrence of multiple lung metastases at 12 months after the surgery and was administrated gefitinib. The lung metastases disappeared at 3 months after the administration of gefitinib. A single metastasis in the left lower lung appearance again and VATS wedge left lung resection as salvage surgery was performed in postoperative 82 months. After salvage surgery, the patient has been followed up without additional treatment and is alive recurrence-free at 19 months.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Pneumonectomia , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 506-510, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816662

RESUMO

Objective: To investigate the synergistic effects of magnolol and gefitinib on non-small cell lung cancer A549 cells. Methods: A549 cells were treated with Magnolol (6.25~500 µmol/L) or gefitinib (6.25~500 µmol/L) for 24 h, respectively, and the cell viability was detected by cell counting Kit-8 (CCK-8) experiment (n=3). Magnolol 100 µmol/L and gefitinib 5 µmol/L were selected in the following experiments (n=3, 24 h). Control group, magnolol group, gefitinib group and magnolol+gefitinib group were set up for factorial analysis. Colony formation experiment was applied to detect the cell proliferation. Western blot was used to detect protein expressions. Flow cytometry was applied to test cell apoptosis and sorting CD44+ and CD133+ cells. Results: Compared with the control group, the colony formation rate of Magnolol or Gefitinib groups was decreased significantly (P<0.05); the apoptosis rate was increased significantly (P<0.05); the number of CD44+ and CD133+ cells was reduced significantly (P<0.05); the expressions of Ki67, PCNA, and stem cell marker proteins SOX2 and OCT4 were down-regulated (P<0.05); and the ratio of Bax/Bcl-2 was increased significantly (P<0.05). Compared with the Magnolol group or Gefitinib group, the Magnolol+Gefitinib group further promoted the above changes (P<0.05), and the apoptosis rate, the ratio of Bax/Bcl-2, SOX2 and OCT4 all showed interactions between magnolol and gefitinib (P<0.05). Conclusion: Magnolol and gefitinib promote the apoptosis of A549 cells and inhibit its stem cell-like properties, and the effect of the two combined is better than separated administration. Magnolol and gefitinib have interactive effects on A549 cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Apoptose , Compostos de Bifenilo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Gefitinibe/farmacologia , Humanos , Lignanas , Neoplasias Pulmonares/tratamento farmacológico
5.
Medicine (Baltimore) ; 100(39): e27289, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596125

RESUMO

RATIONALE: Transformation to small cell lung cancer (SCLC) is one of the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, no standard treatment is available after the transformation. In addition, gastric metastasis of primary lung cancer is rarely observed; thus, little is known about its metastatic characteristics. PATIENT CONCERNS: A 58-year-old male patient was treated with gefitinib (0.25 g /day) as the 1st line treatment due of recurrence after surgical resection for EGFR exon 19 mutation pulmonary adenocarcinoma. However, he experienced recurrence with positive T790 M, and osimertinib (80 mg/day) was administered as the 2nd line therapy. DIAGNOSIS: One year and 6 months after osimertinib initiation, he complained of stomachache, and a diagnostic gastroscopy biopsy confirmed small cell lung cancer in the gastric body, indicating osimertinib-induced phenotypic transformation. INTERVENTIONS AND OUTCOMES: The patient was treated with etoposide and platinum chemotherapy and maintenance therapy with osimertinib. Finally, the patient achieved a partial response after 4 cycles. LESSONS: Timely second biopsies should be considered in the diagnosis of phenotypic transformation. After transformation, chemotherapeutic treatment with etoposide and platinum and maintenance therapy with osimertinib inhibited the progression of the disease.


Assuntos
Adenocarcinoma de Pulmão/patologia , Transformação Celular Neoplásica , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Gástricas/secundário , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/secundário , Resistencia a Medicamentos Antineoplásicos , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico
6.
Molecules ; 26(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34641511

RESUMO

Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Membrana Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/fisiologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Colesterol/metabolismo , Gefitinibe/administração & dosagem , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Tolueno/administração & dosagem , Tolueno/análogos & derivados , Tolueno/farmacologia
7.
Eur J Pharm Sci ; 167: 106004, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520834

RESUMO

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-based molecular targeted therapy are proved to be effective in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutation, its efficacy is limited by the acquired drug resistance. The combination of EGFR-TKIs with photodynamic therapy (PDT) has been explored to combat NSCLC with promising synergistic results. However, hypoxic tumor microenvironment is associated with the development of EGFR-TKIs resistance and severely limits the efficacy of PDT. Here, we synthesized an aptamer modified fluorinated dendrimer (APF) as a drug carrier and prepared nanocomplexes APFHG by encapsulation of gefitinib (Gef) and hematoporphyrin (Hp). APF has good oxygen-carrying capacity, high drug entrapment efficiency, and could release Gef and Hp in response to intracellular pH. APF can specifically recognize EGFR-positive NSCLC cells and effectively improve the tumor hypoxic microenvironment due to the targeting effect of aptamer and the good oxygen-carrying capacity of the fluorinated dendrimer. Under the laser irradiation, APFHG can significantly increase the production of the intracellular reactive oxygen species and produce a synergistic therapeutic effect in inhibition of cellular growth and induction of cell cycle arrest and apoptosis on both Gef-sensitive and Gef-resistant EGFR-mutant NSCLC cells through PDT/molecular targeted therapy. This work indicates that fluorinated dendrimer could be a potent drug delivery platform to overcome hypoxia-related resistance and the co-delivery of EGFR-TKI and photosensitizer by the fluorinated dendrimer could be a promising therapeutic approach for reversal of EGFR-TKIs resistance in EGFR mutation-positive NSCLC.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Dendrímeros , Neoplasias Pulmonares , Fotoquimioterapia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Dendrímeros/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Hematoporfirinas/farmacologia , Hematoporfirinas/uso terapêutico , Humanos , Hipóxia , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Microambiente Tumoral
8.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479918

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Biomater Sci ; 9(21): 7065-7075, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34590101

RESUMO

Drug delivery nanoplatforms have been applied in bioimaging, medical diagnosis, drug delivery and medical therapy. However, insolubility, toxicity, instability, nonspecific targeting and short retention of many hydrophobic drugs limit their extensive applications. Herein, we have constructed a passive targeting and long retention therapeutic nanoplatform of core-shell gefitinib/poly (ethylene glycol)-polytyrosine nanocomplexes (Gef-PY NCs). The Gef-PY NCs have good water-solubility, non-toxicity (correspond to 1/10 dosage of effective gefitinib (hydrochloride) (Gef·HCl) (normal drug administration and slow-release) and high stability (120 days, 80% drug retention at 4 or 25 °C). The core-shell Gef-PY NCs present unexpected kidney targeting and drug slow-release capacity (ca. 72 h). The good water-solubility, non-toxicity and high stability of Gef-PY NCs effectively solve the bottleneck question that Gef-based therapy could be used only in intraperitoneal injection due to its insolubility and severe toxicity. Such excellent properties (e.g., water-solubility, non-toxicity, high stability, kidney targeting and long retention) of Gef-PY NCs create their prominent anti-fibrosis capabilities, such as decreasing approximately 40% tubulointerstitial fibrosis area and 68% expression of collagen I within 7 days. This therapeutic efficacy is well-matched with that of 10 times the dosage of toxic Gef·HCl. It is very hopeful that Gef-PY NCs could realize clinical applications and such a strategy offers an effective route to design high-efficiency treatments for kidney- and tumor-related diseases.


Assuntos
Antineoplásicos , Aminoácidos , Sistemas de Liberação de Medicamentos , Gefitinibe , Água
10.
BMC Cancer ; 21(1): 877, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332557

RESUMO

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. METHODS: The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. DISCUSSION: Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. TRIAL REGISTRATION: This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .


Assuntos
Transferência Adotiva , Carcinoma Pulmonar de Células não Pequenas/terapia , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/terapia , Mutação , Células T Matadoras Naturais/imunologia , Transferência Adotiva/efeitos adversos , Transferência Adotiva/métodos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/etiologia , Terapia Combinada , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Terapia de Alvo Molecular , Células T Matadoras Naturais/metabolismo , Resultado do Tratamento
11.
Sci Rep ; 11(1): 16661, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404849

RESUMO

The return of blood flow to ischemic heart after myocardial infarction causes ischemia-reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia-reperfusion injury. Here we screened for targets for the treatment of ischemia-reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein-protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.


Assuntos
Cardiotônicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Descoberta de Drogas , Receptores ErbB/genética , Hipóxia/tratamento farmacológico , Hipóxia/genética , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Peixe-Zebra
12.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445495

RESUMO

As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR signaling. Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. In this study, we investigated whether the gain-of-function p53 mutation (p53R248Q) overexpression could affect EGFR-related signaling and the corresponding drug inhibition outcome in HGSOC. The targeted inhibition responses of gefitinib and JNJ-26854165, in p53R248Q-overexpressing cells, were extensively evaluated. We found that the phosphorylation of AKT increased when p53R248Q was transiently overexpressed. Immunocytochemistry analysis further showed that upon p53R248Q overexpression, several AKT-related regulatory proteins translocated in unique intracellular patterns. Subsequent analysis revealed that, under the combined inhibition of gefitinib and JNJ-26854165, the cytonuclear trafficking of EGFR and MDM2 was disrupted. Next, we analyzed the gefitinib and JNJ-26854165 responses and found differential sensitivity to the single- or combined-drug inhibitions in p53R248Q-overexpressing cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cistadenocarcinoma Seroso/genética , Mutação com Ganho de Função , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Triptaminas/farmacologia
13.
Eur J Pharm Sci ; 165: 105933, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260895

RESUMO

Generally, two-period cross-over design is used in bioequivalence (BE) study. High intra-subject variability of gefitinib was reported in a clinical BE study, and significant changes in gefitinib exposures were observed among different periods in our previous BE study in dogs. Therefore, commercial gefitinib tablets from the same batch were used in the present study and assigned to two groups: the testing drug (GF1) group and the reference drug (GF2) group. A single-oral-dose, two-period cross-over study with a 7-day washout (approximately 24 half-lives) under fasting condition was conducted in 12 dogs to explore the factors. The results showed that the mean values of AUC(0-t), AUC(0-∞), Cmax and Tmax of these two GF1 and GF2 groups were similar. However, the GF1 and GF2 did not meet the acceptance criteria of bioequivalence with 90% confidence intervals, since the values obtained were 76.22%-117.43% for AUC(0-t) and 87.55%-131.59% for Cmax. ANOVA revealed a significant difference between the two periods (P < 0.05). Interestingly, the mean AUC(0-t) of gefitinib in the period 2 was 2.3-fold greater than that in the period 1, while Cmax in the period 2 was 1.7-fold higher than that in the period 1. However, the volume of distribution was significantly decreased, becoming 0.4-fold lower in the period 2. No statistically significant difference in the half-life and Tmax was observed between the two periods (P < 0.05). The pharmacokinetic alteration might come from the different physiological absorption and/or metabolism between periods. Since a 7-day washout interval was applied, DDI risk from P450s and/or P-gp would not play a significant role in the non-bioequivalence. As regard the variability, the intra-subject variation crossing the periods was much larger than the inter-subject variation within each period. The absorption and/or metabolism function of the gut bacteria might play an important role in the increasing exposure of gefitinib in the second period, especially with the comparison with the analysis from the high-fat-diet treatments in humans. Therefore, further studies might be needed to evaluate whether the assessment of bioequivalence could be facilitated by a much longer washout interval allowing the recovery of gut bacteria.


Assuntos
Estudos Cross-Over , Animais , Área Sob a Curva , Cães , Gefitinibe , Comprimidos , Equivalência Terapêutica
14.
J Cancer Res Clin Oncol ; 147(11): 3245-3254, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34255150

RESUMO

PURPOSE: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) improve the prognosis of lung adenocarcinoma (LUAD). However, the factors affecting its clinical efficacy remain unclear. This study aimed to determine the correlation between Osteopontin (OPN) and EGFR, and explore the inhibitory effect of first-generation TKI gefitinib on LUAD cells. METHODS: The correlation between OPN and EGFR was determined through bioinformatics technology, and the clinical information as well as samples of related patients were collected to verify the relationship between them. Using three different NSCLC cell lines A549, H1299 and PC9, we studied the effects of OPN expression and EGFR phosphorylation on the first-generation TKI's efficacy in vitro. RESULTS: Our data revealed that OPN staining positively linked to a more advanced clinical stage. Compared with the control group, LUAD cells with elevated OPN levels are more sensitive to the growth inhibitory effect of TKI. Knocking down of OPN decreased the response of cells to gefitinib. Besides, OPN also upregulated the phosphorylation of EGFR, thereby affecting the effect of TKI. CONCLUSION: OPN enhanced the sensitivity of LUAD cells to gefitinib by promoting EGFR phosphorylation. OPN may be a potential target for evaluating TKI efficacy and a potential target for molecular therapy.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Osteopontina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosforilação
15.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34212976

RESUMO

The present study aimed to investigate the effects of a gefitinib derivative, LPY­9, on the proliferation, apoptosis and migration of human glioma cell line U251­MG by CCK8, Transwell or flow cytometry, and the effect of LPY­9 on the activity of caspase­3 enzyme and related proteins in the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways by western blot and ELISA. It was found that LPY­9 exhibited higher a inhibitory effect on the proliferation of U251­MG cell lines compared with gefitinib and it also exhibited a certain dose­dependence. Following LPY­9 treatment, typical apoptotic morphology was observed under the microscope after Giemsa staining. LPY­9 induced apoptosis at low concentration, and the activity of caspase­3 enzyme increased with the increase in drug concentration, significantly inhibiting the secretion of VEGF in a dose­dependent manner. The effect was notably more evident compared with gefitinib at the same concentration. The expression level of caspase­3 and cleaved caspase­3 increased with the increase in LPY­9 concentration; however, expression levels of VEGF, EGFR, phosphorylated AKT and PI3K decreased with the increase of LPY­9 concentration and no change was observed in the expression level of AKT. LPY­9 inhibited the proliferation of the human glioma cell line U251­MG, promoted apoptosis and effectively inhibited the migration of U251­MG cells. The effect of LPY­9 was more noticeable compared with gefitinib. The results of the present study may provide a foundation for further study and clinical research of this as an anti­tumor drug in animal models.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Gefitinibe/química , Gefitinibe/farmacologia , Glioma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioma/genética , Humanos , Fosforilação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201116

RESUMO

The methylated resveratrol analogue 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214) has been revealed to exert the anti-cancer activity by a block of the cell cycle at the G2/M phase, apoptosis induction, and metastasis inhibition. These biological events may be involved in crosstalk with the epidermal growth factor receptor (EGFR), which belongs to the ErbB family of receptor tyrosine kinases. Several cancer therapeutic approaches employ small molecules capable of inhibiting tyrosine kinases (e.g., gefitinib). According to more recent reports, combining gefitinib with chemotherapeutics, such as cisplatin, seems to be more effective than monotherapy. The present study aimed to assess the molecular mechanism of the potential anti-proliferative activity of individual and combined treatments with DMU-214 and gefitinib in SCC-25 and CAL-27 human tongue cancer cell lines. We showed for the first time the anti-cancer effects of DMU-214, gefitinib, and their combination in tongue cancer cells triggered via cell cycle arrest, apoptosis induction, and inhibition of the EGFR signaling pathway. The anti-proliferative effects of DMU-214 and gefitinib are also suggested to be related to the EGFR and EGFRP (phosphorylated epidermal growth factor receptor) expression status since we found significantly weaker cytotoxic activity of the compounds tested in SCC-25 cells, which overexpressed EGFR and EGFRP proteins.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Língua/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Gefitinibe/administração & dosagem , Humanos , Resveratrol/administração & dosagem , Resveratrol/análogos & derivados , Neoplasias da Língua/tratamento farmacológico , Neoplasias da Língua/genética , Neoplasias da Língua/metabolismo , Células Tumorais Cultivadas
17.
Cells ; 10(6)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208765

RESUMO

BACKGROUND: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs (miR-21, miR-27a and miR-181a) as a surrogate for predicting EGFR-TKI performance in EGFR-mutated NSCLC patients. METHODS: Plasma samples of 39 advanced EGFR-mutated NSCLC patients treated with EGFR-TKIs were collected at different points in time and miRNA levels were assessed by RT-PCR. RESULTS: Higher basal values of miR-21 were reported in patients who achieved a partial/complete response (PR/CR) compared to those with stability/progression of disease (SD/PD) (p = 0.011). Along the same line, patients who experienced a clinical benefit lasting at least six months displayed higher basal levels of circulating miR-21 (p = 0.039). However, dynamic evaluation of miRNA values after two months from the start of EGFR-TKI treatment showed that patients who experienced SD had an increase in miR-21 levels (Fold Change [FC] = 2.6) compared to patients achieving PR/CR (p = 0.029). The same tendency was observed for miR-27a (FC = 3.1) and miR-181a (FC = 2.0), although without reaching statistical significance. Remarkably, preclinical studies showed an increase in miR-21 levels in NSCLC cells that became resistant after exposure to EGFR-TKIs. CONCLUSIONS: Our study provides interesting insights on the role of circulating miRNAs, in particular miR-21, and their dynamic change over time in predicting EGFR-TKI response in EGFR-mutated NSCLC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/sangue , Adulto , Afatinib/uso terapêutico , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , MicroRNA Circulante/sangue , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
18.
J Control Release ; 337: 329-342, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34311024

RESUMO

Lung cancer is still the main cause of cancer-related deaths worldwide. Its treatment generally includes surgical resection, immunotherapy, radiotherapy, and chemo-targeted therapies such as the application of tyrosine kinase inhibitors. Gefitinib (GEF) is one of them, but its poor solubility in gastric fluids weakens its bioavailability and therapeutic activity. In addition, like all other chemotherapy treatments, GEF administration can cause damage to healthy tissues. Therefore, the development of novel GEF delivery systems to increase its bioavailability and distribution in tumor site is highly demanded. Herein, an innovative strategy for GEF delivery, by functionalizing PLGA nanoparticles with p28 (p28-NPs), a cell-penetrating peptide derived from the bacterial protein azurin, was developed. Our data indicated that p28 potentiates the selective interaction of these nanosystems with A549 lung cancer cells (active targeting). Further p28-NPs delivering GEF (p28-NPs-GEF) were able to selectively reduce the metabolic activity of A549 cells, while no impact was observed in non-tumor cells (16HBE14o-). In vivo studies using A549 subcutaneous xenograft showed that p28-NPs-GEF reduced A549 primary tumor burden and lung metastases formation. Overall, the design of a p28-functionalized delivery nanosystem to effectively penetrate the membranes of cancer cells while deliver GEF could provide a new strategy to improve lung cancer therapy.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Nanopartículas , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Gefitinibe , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Carga Tumoral
20.
BMC Cancer ; 21(1): 652, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074257

RESUMO

BACKGROUND: Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. METHODS: To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. RESULTS: Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. CONCLUSIONS: Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Mutação com Ganho de Função , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Lapatinib , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Mutação Puntual , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Esferoides Celulares , Regulação para Cima
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