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1.
Cells ; 11(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35805163

RESUMO

Integrin ß3 plays a key role in the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), but the development of integrin ß3 inhibitors has been stalled due to the failure of phase III clinical trials for cancer treatment. Therefore, it is imperative to find a potentially effective solution to the problem of acquired resistance to EGFR-TKI for patients with integrin-ß3 positive non-small-cell lung cancer (NSCLC) by exploring novel downstream targets and action mechanisms of integrin ß3. In the present study, we observed that the expression of integrin ß3 and AXL was significantly upregulated in erlotinib-resistant NSCLC cell lines, which was further confirmed clinically in tumor specimens from patients with NSCLC who developed acquired resistance to erlotinib. Through ectopic expression or knockdown, we found that AXL expression was positively regulated by integrin ß3. In addition, integrin ß3 promoted erlotinib resistance in NSCLC cells by upregulating AXL expression. Furthermore, the YAP pathway, rather than pathways associated with ERK or AKT, was involved in the regulation of AXL by integrin ß3. To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial-mesenchymal transformation and cell migration induced by integrin ß3. In conclusion, integrin ß3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin ß3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Integrina beta3/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
2.
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
3.
Cancer Chemother Pharmacol ; 90(2): 115-123, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35821437

RESUMO

PURPOSE: To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. PATIENTS AND METHODS: EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. RESULTS: Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683-63,257 ng·h/mL) and 2338 ng·h/mL (581-5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). CONCLUSION: The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. CLINICAL TRIALS REGISTRATION NUMBER: UMIN000012862.


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 , Cloridrato de Erlotinib/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
4.
Cancer Chemother Pharmacol ; 90(2): 137-148, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35841410

RESUMO

PURPOSE: In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY. METHODS: Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by Cmin,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only. RESULTS: Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury. CONCLUSIONS: No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02411448.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Hipertensão , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Cloridrato de Erlotinib , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação
5.
Front Biosci (Landmark Ed) ; 27(7): 219, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35866410

RESUMO

BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children and represent a variety of diseases and molecular subtypes. This study sought to evaluate a rapid immunohistochemistry testing panel to aid in therapy selection at the time of malignant tumor recurrence. METHODS: With IRB approval and appropriate informed consent, we conducted a single-institution prospective clinical trial of selected kinase inhibitor therapy. A laboratory-developed immunohistochemical testing panel was performed on tumor tissue, and therapy with one of four small molecule inhibitors was recommended in combination with oral chemotherapy consisting of temozolomide and etoposide. RESULTS: All 20 enrolled subjects were assigned to Everolimus (n = 4), Erlotinib (n = 6) or Dasatinib (n = 10); 90% (18/20) within the pre-specified 14-day feasibility time period. Only two subjects elected treatment on study, 8 received targeted treatment based on testing results either alone (n = 5) or in combination with chemotherapy (n = 3). Other subjects received chemotherapy alone (n = 7), surgery alone (n = 2) or no further therapy (n = 3). Immunohistochemical targets were associated with correlative genetic changes in 28% (5/18) of those evaluated. CONCLUSIONS: It was feasible to rapidly select targeted therapy in recurrent pediatric brain tumors, but not feasible to treat with a uniform combination treatment regimen.


Assuntos
Neoplasias Encefálicas , Everolimo , Neoplasias Encefálicas/tratamento farmacológico , Criança , Dasatinibe/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Everolimo/uso terapêutico , Estudos de Viabilidade , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Seleção de Pacientes , Estudos Prospectivos , Sorafenibe/uso terapêutico , Adulto Jovem
6.
Mar Drugs ; 20(7)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35877711

RESUMO

The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Glioblastoma , Neoplasias Pulmonares , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib , Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Macrolídeos , Mamíferos/metabolismo , Camundongos , Fosforilação
7.
Sci Rep ; 12(1): 12820, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896603

RESUMO

The 4-anilinoquin(az)oline is a well-known kinase inhibitor scaffold incorporated in clinical inhibitors including gefitinib, erlotinib, afatinib, and lapatinib, all of which have previously demonstrated activity against chordoma cell lines in vitro. We screened a focused array of compounds based on the 4-anilinoquin(az)oline scaffold against both U-CH1 and the epidermal growth factor receptor (EGFR) inhibitor resistant U-CH2. To prioritize the hit compounds for further development, we screened the compound set in a multiparameter cell health toxicity assay. The de-risked compounds were then screened against a wider panel of patient derived cell lines and demonstrated low micromolar efficacy in cells. We also investigated the properties that gave rise to the toxophore markers, including the structural and electronic features, while optimizing for EGFR in-cell target engagement. These de-risked leads present a potential new therapeutic avenue for treatment of chordomas and new chemical tools and probe compound 45 (UNC-CA359) to interrogate EGFR mediated disease phenotypes.


Assuntos
Compostos de Anilina/farmacologia , Cordoma , Neoplasias Pulmonares , Quinazolinas/farmacologia , Cordoma/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico
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.
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
10.
J Microencapsul ; 39(4): 394-408, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35748819

RESUMO

The use of magnetic nanoparticles (MNPs) in biomedical applications has been wildly opted due to their unique properties. Here, we designed MNPs loaded with erlotinib (ERL/SPION-Val-PEG) and conjugated them with anti-mucin16 (MUC16) aptamer to introduce new image-guided nanoparticles (NPs) for targeted drug delivery as well as non-invasive magnetic resonance imaging (MRI) contrast agents. Also, the combination of our nanosystem (NS) along with L-Asparaginase (L-ASPN) led to synergistic effects in terms of reducing cell viability in ovarian cancer cells, which could suggest a novel combination therapy. The mean size of our NS was about 63.4 ± 3.4 nm evaluated by DLS analysis and its morphology was confirmed using TEM. Moreover, the functional groups, as well as magnetic properties of our NS, were examined by FT-IR and VSM tests, respectively. The loading efficacy of erlotinib on MNPs was about 80% and its release reached 70.85% over 7 days in the pH value of 5.4. The MR images and flow cytometry results revealed that the cellular uptake of ERL/SPION-Val-PEG-MUC16 NPs in cells with MUC16 overexpression was considerably higher than unarmed NPs. In addition, T2-weight MR images of ovarian cancer-bearing mice indicated significant signal intensity changes at the tumour site 4 h after intravenous injection compared to the non-target MNPs. Our data suggest ERL/SPION-Val-PEG NPs as an image-guided co-drug delivery system for ovarian cancer.


Assuntos
Nanopartículas de Magnetita , Nanopartículas , Neoplasias Ovarianas , Animais , Asparaginase , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Camundongos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Thorac Cancer ; 13(15): 2192-2200, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35768976

RESUMO

BACKGROUND: In the phase II JO25567 study (JapicCTI-111390), erlotinib plus bevacizumab demonstrated a significant clinical benefit in Japanese patients with epidermal growth factor receptor mutation-positive (EGFR+) non-small cell lung cancer (NSCLC). Here, we present an exploratory analysis investigating the impact of baseline pleural/pericardial effusion (PPE) on patient outcomes. METHODS: Patients with stage IIIB/IV or postoperative recurrent EGFR+ NSCLC were randomized 1:1 to receive erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 3 weeks) or erlotinib monotherapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were evaluated according to the presence or absence of baseline PPE. RESULTS: The population comprised 152 patients, 66 with baseline PPE and 86 without. Median PFS was longer with erlotinib plus bevacizumab than with erlotinib alone, with (hazard ratio [HR] 0.45; 95% confidence interval [CI]: 0.25-0.82) or without (HR 0.62; 95% CI: 0.37-1.04) baseline PPE. Median OS was also prolonged with erlotinib plus bevacizumab relative to erlotinib regardless of the presence (HR 0.82; 95% CI: 0.46-1.47) or absence (HR 0.84; 95% CI: 0.46-1.55) of baseline PPE. ORR was higher with erlotinib plus bevacizumab (70.0%) than with erlotinib (55.6%) in patients with baseline PPE, but similar (68.9% vs. 70.7%) in patients without. Most common grade ≥3 adverse events were hypertension and rash in the erlotinib plus bevacizumab arm, and rash in the erlotinib arm, regardless of baseline PPE status. CONCLUSIONS: Erlotinib plus bevacizumab may be a beneficial treatment strategy in patients with EGFR+ NSCLC, especially for those with baseline PPE.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Exantema , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/efeitos adversos , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Humanos , Neoplasias Pulmonares/metabolismo , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico
12.
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
13.
Clin Transl Med ; 12(5): e876, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35605028

RESUMO

OBJECTIVE: Apurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin-6 (IL-6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL-6 signalling in Erlotinib resistance of non-small cell lung cancer (NSCLC). METHODS: We selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib-resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib-sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC-EVs) and RCSCs (RCSC-EVs) and co-cultured with RCSCs with or without short hairpin RNA (shRNA)-targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL-6/STAT3 signalling. RESULTS: It was found that NSCLC cells could internalize both RCSC-EVs and PCSC-EVs. RCSC-EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL-6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL-6/STAT3 signalling. Additionally, shAPE1-loaded RCSC-EVs suppressed the Erlotinib resistance of NSCLC via the IL-6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation. CONCLUSIONS: Collectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL-6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib-resistant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , 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 , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/uso terapêutico , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Humanos , Interleucina-6/metabolismo , Interleucina-6/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/uso terapêutico
14.
Drug Des Devel Ther ; 16: 1457-1471, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35607598

RESUMO

Introduction: Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents. Methods: Different thiazolyl-pyrazoline derivatives (7a-o) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives (7g and 7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines 7b, 7g, 7l, and 7m in the EGFR active pocket (PDB ID: 1M17). Results: Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC50 arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) demonstrated significant sub-micromolar EGFR inhibitory actions with IC50 values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC50 =57 nM). Discussion: Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC50 = 3.92 and 6.53 µM) and T-47D cells (IC50 = 0.88 and 0.75 µM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.


Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias Pulmonares , Tiazóis/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
15.
Int J Pharm ; 622: 121852, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35618179

RESUMO

The present investigation demonstrates the preparation of solid self nanoemulsfying drug delivery system (sSNEDDS) to enhance stability and bioavailability of Erlotinib (ERL) via the oral route. Capmul®MCM EP (CPM EP, oil), Cremophor® RH 40 (CMR RH 40, surfactant), and LBF CS (LBF CS, cosurfactant) were chosen as chief components for preparing Liquids SNEDDS (L-ERL-SNEDDS) based on solubility and emulsion forming ability. Pseudo ternary phase diagram and constrained mixture designs were applied to identify the self-emulsifying area and it was found that CPM EP, CMR RH 40, and LBF CS in the ratio of 59:11:30 showed optimized particle size (110.08 nm), with narrow PDI (0.114) and high ERL loading capacity (14.31 mg/g). Adsorption method was implemented for solidification of L-ERL-SNEDDS. Among various solid carriers were studied, Aerosil® 200 (A200) was finalized based on free flowing property and reconstitution ability. DSC and XRD studies revealed that crystallinity of drug was reduced in developed system. The developed formulation (named as, A200-ERL-sSNEDDS) showed increased cytotoxicity and apoptosis in PANC-1 and MIA PaCa-2 cells. Pharmacokinetic studies revealed ∼2.2 times increase in AUC0-∞values in case of A200-ERL-sSNEDDS as compared to free ERL. Thus current strategy can be extrapolated for delivering of poorly soluble drugs via oral route.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Administração Oral , Animais , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos/métodos , Emulsões , Cloridrato de Erlotinib , Tamanho da Partícula , Ratos , Ratos Wistar , Solubilidade
16.
Sci Rep ; 12(1): 8007, 2022 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-35568782

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho-receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolinas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/farmacologia , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Hepáticas/patologia , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Espécies Reativas de Oxigênio/farmacologia
17.
Cells ; 11(10)2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35626731

RESUMO

NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4-5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1-8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan-Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408781

RESUMO

The epithelial-to-mesenchymal transition (EMT) is important for morphogenesis during development and is mainly induced by transforming growth factor (TGF)-ß. In lung cancer, EMT is characterized by the transformation of cancer cells into a mobile, invasive form that can transit to other organs. Here, using a non-small cell lung cancer (NSCLC) cell line, we evaluated the EMT-related effects of the epidermal growth factor receptor inhibitor erlotinib alone and in combination with cilengitide, a cyclic RGD-based integrin antagonist. Erlotinib showed anti-proliferative and inhibitory effects against the TGF-ß1-induced EMT phenotype in NSCLC cells. Compared with erlotinib alone, combination treatment with cilengitide led to an enhanced inhibitory effect on TGF-ß1-induced expression of mesenchymal markers and invasion in non-small cell lung cancer A549 cells. These results suggest that cilengitide could improve anticancer drug efficacy and contribute to improved treatment strategies to inhibit and prevent EMT-based cancer progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/genética , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Venenos de Serpentes , Fator de Crescimento Transformador beta1/metabolismo
19.
Int J Pharm ; 619: 121722, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35395363

RESUMO

Using an artificial stomach and duodenum (ASD), we investigated the pH-dependent precipitation of erlotinib (ERL) during dissolution in the gastrointestinal (GI) tract by varying the rate of gastric fluid secretion (RGFS). Results show that decreasing RGFS from 2.5 to 0.5 mL/min leads to an increased degree of supersaturation in the duodenum fluid due to elevated pH, resulting in precipitation of ERL and a reduced area under the curve (AUC) of the concentration - time profiles from 14,000 to 3,000 (µg‧min)/mL. Such a change in AUC is expected to lower the bioavailability of ERL, a BCS II drug, in patients with a low RGFS. This example demonstrates the potential use of ASD as an effective tool for guiding the efficient development of robust tablet formulations by better understanding the impact of GI tract pH on the fate of drugs in the duodenal fluid.


Assuntos
Duodeno , Suco Gástrico , Administração Oral , Cloridrato de Erlotinib , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , Estômago
20.
Sci Rep ; 12(1): 7002, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488047

RESUMO

Gefitinib and erlotinib are the first-line tyrosine kinase inhibitors (TKI) for advanced non-small-cell lung cancer. However, co-administration of either drug with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) may reduce TKI's bioavailability. Therefore, we aimed to investigate the effects of these drug-drug interactions. We surveyed nationwide population-based databases between Jan 1, 2010, and Dec 30, 2018. Newly diagnosed patients with advanced lung adenocarcinoma who received first-line gefitinib or erlotinib were identified. Effects on overall survival (OS) and time to next treatment (TTNT) association between PPIs or H2RAs and co-administrated gefitinib or erlotinib were evaluated. PPIs or H2RAs users were defined if the period overlapped with TKIs by ≥ 20%. A total of 4340 gefitinib and 1635 erlotinib users were included. PPI group had the shortest median OS and TTNT compared to the H2RA and non-user groups (in gefitinib cohort: OS: 14.35 vs. 17.67 vs. 21.87 months; P < 0.0001, TTNT: 8.47 vs. 10.78 vs. 10.33 months; P < 0.0001); (in erlotinib cohort: OS: 16.97 vs. 20.07 vs. 23.92 months; P < 0.0001, TTNT: 9.06 vs. 11.85 vs. 10.90 months; P = 0.0808). Compared with the non-user group, the adjusted hazard ratio (aHR) of the PPI group in the gefitinib was 1.58 on OS (95% CI 1.42-1.76), 1.37 on TTNT (95% CI 1.24-1.52); in the erlotinib was 1.54 on OS (95% CI 1.30-1.82) and 1.19 on TTNT (95% CI 1.01-1.39). Concurrent use of PPIs with first-line gefitinib or erlotinib therapy was associated with a worse OS and TTNT in patients with lung adenocarcinoma harboring EGFR mutations.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/induzido quimicamente , Adenocarcinoma de Pulmão/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB , Cloridrato de Erlotinib , Gefitinibe/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases , Inibidores da Bomba de Prótons/uso terapêutico , Quinazolinas
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