Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Anticancer Res ; 39(7): 3785-3793, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262905

RESUMO

BACKGROUND/AIM: This study investigated drugs able to sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to vincristine or eribulin treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: Eight tyrosine kinase inhibitors (lapatinib, gefitinib, imatinib, erlotinib, nilotinib, pazopanib, cediranib, and vandetanib) and one serine/threonine kinase inhibitor (selumetinib) were evaluated for their sensitizing effects on vincristine-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were further performed to investigate their mechanisms of action. RESULTS: Co-treatment of KBV20C cells with lapatinib, gefitinib, imatinib, or erlotinib at low doses highly sensitized them to vincristine treatment. These drugs reduced cellular viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In a detailed quantitative analysis using lower doses, we demonstrated that lapatinib, with high P-gp inhibitory activity, yielded the best pairing for sensitizing P-gp-overexpressing KBV20C cells to vincristine. Co-treatment with eribulin and lapatinib, gefitinib, or erlotinib also increased the sensitivity of KBV20C cells, suggesting that they can be combined with other antimitotic drugs to sensitize resistant cancer cells. Lapatinib was shown to have a higher P-gp-inhibitory activity than verapamil, even at lower doses, indicating that its sensitizing of cells to vincristine involves its P-gp-inhibitory effects. However, interestingly, imatinib- and erlotinib-sensitizing of cells to vincristine appears to be independent of their P-gp inhibition. CONCLUSION: These findings provide valuable information regarding the sensitizing of drug-resistant cells and indicate that imatinib and erlotinib may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.


Assuntos
Antimitóticos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Gefitinibe/farmacologia , Humanos , Lapatinib/farmacologia
3.
J Toxicol Sci ; 44(6): 435-440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168030

RESUMO

Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.


Assuntos
Antineoplásicos/farmacologia , Caspase 8/metabolismo , Proteína Ligante Fas/fisiologia , Gefitinibe/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Proteínas de Choque Térmico HSP72/metabolismo , Humanos , Camundongos
4.
Carbohydr Polym ; 216: 204-212, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047058

RESUMO

Sulfated polysaccharides (SPSs) are polysaccharides (PSs) with high sulfate functionalization and possess bioactivities. This study aimed to increase the sulfate content of SPSs in Antrodia cinnamomea through sulfate feeding. Feeding A. cinnamomea with sodium thiosulfate was found to increase yields of PSs and SPSs in A. cinnamomea. The SPSs thus obtained (ST-SPS) were further isolated, showing enhanced sulfate content of 2.5 mmol/g. Sodium thiosulfate induced changes in molecular weight from 320 kDa to 1342 kDa, and area percentage of low-molecular-weight ST-SPS (< 20 kDa) was decreased. Functional studies revealed that sodium thiosulfate increased the ST-SPS anticancer efficacy in cancer cells via inhibition of EGFR/AKT signaling. Moreover, the ST-SPS enhanced synergistically cisplatin-, gefitinib- and 5 FU-induced cytotoxic effects in lung cancer H1975 cells and colon cancer CT26 cells. This study is the first to demonstrate that sodium thiosulfate induced changes in properties of A. cinnamomea with the anticancer mechanisms of ST-SPS.


Assuntos
Antineoplásicos/farmacologia , Antrodia/química , Antrodia/metabolismo , Polissacarídeos/farmacologia , Ésteres do Ácido Sulfúrico/farmacologia , Tiossulfatos/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Fluoruracila/farmacologia , Gefitinibe/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Peso Molecular , Fosforilação/efeitos dos fármacos , Polissacarídeos/biossíntese , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Ésteres do Ácido Sulfúrico/química , Ésteres do Ácido Sulfúrico/isolamento & purificação , Ésteres do Ácido Sulfúrico/metabolismo
5.
Zhongguo Fei Ai Za Zhi ; 22(5): 255-263, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31109434

RESUMO

BACKGROUND: Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells. METHODS: PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression. RESULTS: In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins. CONCLUSIONS: The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos
6.
Cell Prolif ; 52(4): e12636, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094020

RESUMO

OBJECTIVES: We previously reported that Golgi phosphoprotein 3 (GOLPH3) promotes glioma progression by inhibiting EGFR endocytosis and degradation, leading to EGFR accumulation and PI3K-AKT pathway over-activation. In the current study, we examine whether GOLPH3 affects the response of glioma cells to gefitinib, an EGFR selective inhibitor. MATERIALS AND METHODS: The expression of GOLPH3 and EGFR in glioma cells was detected by immunofluorescence and immunoblotting. The cell viability or growth in vitro was determined by CCK-8, EdU incorporation and clonogenic assays. The primary glioma cells were cultured by trypsin and mechanical digestion. The transwell invasion assay was used to examine the primary glioma cell motility. Intracranial glioma model in nude mice were established to explore the sensitivity of gefitinib to GOLPH3 high cancer cells in vivo. RESULTS: Both the immortalized and primary glioma cells with GOLPH3 over-expression hold higher EGFR protein levels on the cell membrane and exhibited higher sensitivity to gefitinib. In addition, primary glioma cells with higher GOLPH3 level exhibited stronger proliferation behaviour. Importantly, GOLPH3 enhanced the anti-tumour effect of gefitinib in vivo. Consistently, after gefitinib treatment, tumours derived from GOLPH3 over-expression cells exhibited lower Ki67-positive and higher cleaved caspase-3-positive cells than control tumours. CONCLUSIONS: Our results demonstrate that GOLPH3 increases the sensitivity of glioma cells to gefitinib. Our study provides foundation for further exploring whether GOLPH3 high gliomas will be more sensitive to anti-EGFR therapy in clinic and give ideas for developing new possible treatments for individual glioma patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Gefitinibe/farmacologia , Glioma/tratamento farmacológico , Glioma/metabolismo , Proteínas de Membrana/metabolismo , Animais , Neoplasias Encefálicas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Hum Cell ; 32(3): 360-366, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020605

RESUMO

Gefitinib is the first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), which is used in the treatment of NCSLC patients through interrupting EGFR signaling pathway. Although gefitinib prolongs patients' progression-free survival (PFS), acquired resistance occurs in advanced NSCLC patients. In this study, we mainly investigated the effects of antagonist for ghrelin-R (D-lys-3-GHRP-6) on conquering acquired gefitinib resistance in human lung cancer cells. We found that GHSR was overexpressed in our established HCC827/GR cells compared with parental cells, accompanied with increase of p-AKT and p-ERK1/2. Treatment of D-lys-3-GHRP-6 significantly decreased p-AKT and p-ERK1/2 expression in HCC827/GR cells. H1650 cells and HCC827/GR cells were treated with control, gefitinib, D-lys-3-GHRP-6 and D-lys-3-GHRP-6 + gefitinib, respectively. In H1650 and HCC827/GR cells, combination of D-lys-3-GHRP-6 and gefitinib significantly inhibited cell proliferation and Bcl2 protein level, induced the cell apoptosis and cleaved-caspase3 protein level compared with control group, while there was no significant difference between control and gefitinib group.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/administração & dosagem , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Grelina/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Biomed Pharmacother ; 114: 108820, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30951947

RESUMO

Current treatment of advanced-stage nasopharyngeal carcinoma (NPC) is not satisfactory. Here, we developed a folic acid (FA) modified, gefitinib (GEF) and yttrium 90 (Y90) co-loaded, core-shell structured lipid-polymer hybrid nanoparticles (FA-GEF-Y90-LPNP). The size and zeta potential, drug release behavior, and uptake by tumor cells were investigated. The antitumor efficiency and toxicity of LPNP were evaluated in cancer cells and in tumor bearing mice. FA-GEF-Y90-LPNP with a mean size of 150 nm and zeta potential of -40 mV was able to enhance the accumulation in the NPC cells and exhibited the highest cytotoxicity. The AUC and T1/2 of FA-GEF-Y90-LPNP group was 217.62 ± 10.32 mg/L.h and 12.09 ± 0.43 h, respectively. FA-GEF-Y90-LPNP exhibited the best in vivo tumor inhibition ability, leading to a 221.2 ± 13.5 mm3 of tumor volume at day 21. FA-GEF-Y90-LPNP treatment resulted in almost no difference in the body weight. This may be the evidence that the systemic toxicity of FA-GEF-Y90-LPNP is low and may be used as safety system for the treatment of NPC.


Assuntos
Ácido Fólico/farmacologia , Gefitinibe/farmacologia , Nanopartículas/química , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Polímeros/química , Radioisótopos de Ítrio/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia/métodos , Portadores de Fármacos/química , Humanos , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula
9.
Arch Pharm (Weinheim) ; 352(5): e1800381, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012144

RESUMO

Drug latentiation is a process of modifying a drug molecule structurally to improve its binding affinity as well as increasing the drug-receptor interactions and potentiate its therapeutic potential. In the quest for discovering more potent epidermal growth factor receptor (EGFR) inhibitors, gefitinib-based derivatives were designed by simple structural modification at the secondary amine of gefitinib by N-alkylation. Three gefitinib derivatives (gefitinib-NB, -NP, and -NIP) were synthesized by N-alkylation and phase transfer catalysis. Structural characterization, physicochemical parameters such as solubility, log P, and p K a were determined. Molecular docking studies were carried out to investigate the binding interactions at the active site. Further drug-bovine serum albumin (BSA) protein and drug-calf thymus (CT) DNA interactions were performed to understand the pharmacokinetics of the synthesized derivatives. All the compounds were screened for preliminary in vitro cytotoxic activity against A549, A431 lung, and MDA-MB-231 breast cancer cell lines by MTT assay. The gefitinib-NP and gefitinib-NB derivatives exhibited strong cytotoxic activity compared with gefitinib. They also showed higher drug-BSA and drug-DNA interactions. Molecular docking studies showed the orientation and binding interactions with the EGFR as well as with BSA and CT DNA. The results establish a strong correlation between the experimental and molecular docking studies. EGFR inhibition studies were also carried out for the derivatives and we identified the NP derivative of gefitinib as a potential lead compound. The gefitinib-based derivatives reported herein are cytotoxic agents and can be tested for further pharmacokinetic profiles and toxicity studies which might be helpful for designing more potent gefitinib-based derivatives in the future.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Gefitinibe/análogos & derivados , Gefitinibe/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Gefitinibe/síntese química , Gefitinibe/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
10.
J Ethnopharmacol ; 237: 128-140, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-30910577

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Xiaoji decoction (XJD) has long been used for cancer treatment. However, the molecular mechanisms underlying the effects of this medicine, particularly to enhance the efficiency of EGFR-TKI in the treatment of lung cancer have not been well elucidated. MATERIALS AND METHODS: Cell viability and cell cycle distribution were detected by MTT assay and flow cytometry, respectively. The phosphorylation of ERK1/2 and protein levels of SP1 and EP4 were determined by Western blot. The expression of the HOX transcript antisense RNA (HOTAIR) was measured by qRT-PCR. Transient transfection experiments were used to overexpress the HOTAIR, SP1 and EP4 genes. The interaction between HOTAIR and SP1 were further examined via RNA immunoprecipitation (RIP) assay. A tumor xenograft model was used to confirm the in vitro findings. RESULTS: We showed that XJD inhibited growth and induced cell arrest of human non-small cell lung cancer (NSCLC) cells. We also found that XJD increased the phosphorylation of ERK1/2 and inhibited levels of HOTAIR and SP1, EP4 proteins, which were blocked by inhibitor of MEK/ERK. There was reciprocal interaction between HOTAIR and SP1. Silencing of HOTAIR reduced EP4 protein levels and repressed the growth of NSCLC cells, while overexpression of HOTAIR and SP1 overcame XJD-reduced EP4 protein expression. Additionally, excessive expressed EP4 reversed the effect of XJD on cell growth. Importantly, there was synergy of XJD with another cancer treatment drug, EGFR-TKI gefitinib, in this process. We also found that XJD inhibited tumor growth in a xenograft nude mice model. CONCLUSIONS: Our results show that XJD inhibits NSCLC cell growth via ERK1/2-mediated reciprocal repression of HOTAIR and SP1 protein expression, followed by reduced EP4 gene expression. XJD and gefitinib exhibit synergy in this process. The in vitro and in vivo study provides a novel mechanism by which XJD enhances the growth inhibitory effect of gefitinib in gefitinib-resistant NSCLC cells.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas , Gefitinibe , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , RNA Longo não Codificante/fisiologia , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Fator de Transcrição Sp1/fisiologia
11.
Biomed Pharmacother ; 111: 1132-1140, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841426

RESUMO

Lung cancer remains the leading cause of cancer death worldwide, and the current therapy seems to have reached a plateau due to toxicities and acquired resistance. Therefore, exploration of novel therapeutic avenues may be useful. Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula first described approximately one thousand years, is often prescribed for cancer patients as a complementary therapy. However, whether SJZ benefits cancer patients as well as the main active constituents and its regulatory mechanism in combination with anticancer drugs remains unknown. Here, we investigated the anti-lung cancer potency and underlying mechanisms of the combination of gefitinib plus SJZ in mice with Lewis lung carcinoma (LLC), using histopathology and an integrated strategy of metabolomics and network pharmacology. The results showed that SJZ significantly enhanced gefitinib suppressing tumor growth and inhibiting LLC metastasis in LLC-bearing mice. Furthermore, 9 potential metabolomics biomarkers that differentially expressed in the SJZ/gefitinib group compared to the SJZ group or gefitinib group were identified by untargeted metabolomics, mainly involved three pathways: tricarboxylic acid cycle, tyrosine and tryptophan biosynthesis metabolism and linoleic acid metabolism. Five active ingredients, kaempferol, ginsenoside Rf, caprylic acid, lauric acid and naringenin, acted directly on 9 targets and regulated 4 out of 9 metabolites. Our results indicated that SJZ enhanced the anti-lung cancer effects of gefitinib via the key targets ABCG2, ABCC1, ABAT, GSR, CYP1A2, ALOX5, CYP3A4, PLA2G1B and PLA2G2A and the key metabolites 2-oxoglutarate, taurocholic acid, oxidized glutathione and linoleic acid. This work illustrated the modulatory properties of SJZ, which enhanced the anticancer effects of gefitinib, using metabolomics and network pharmacology analyses, and provided insights into underlying the mechanism the active ingredients of SJZfor the treatment of lung cancer in combination with gefitinib.


Assuntos
Antineoplásicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa/métodos , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL
12.
Oncol Rep ; 41(4): 2194-2208, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816530

RESUMO

MicroRNAs (miRNAs or miRs) contribute to the development of various malignant neoplasms, including glioblastoma multiforme (GBM). The present study aimed to explore the pathogenesis of GBM and to identify latent therapeutic agents for patients with GBM, based on an in silico analysis. Gene chips that provide miRNA expression profiling in GBM were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) were also determined via the RobustRankAggreg algorithm. The target genes of DEMs were predicted and then intersected with GBM­associated genes that were collected from the Gene Expression Profiling Interactive Analysis. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the overlapping genes were then performed. Simultaneously, a connectivity map (CMap) analysis was performed to screen for potential therapeutic agents for GBM. A total of 10 DEMs (hsa­miR­196a, hsa­miR­10b, hsa­miR­196b, hsa­miR­18b, hsa­miR­542­3p, hsa­miR­129­3p, hsa­miR­1224­5p, hsa­miR­876­3p and hsa­miR­770­5p) were obtained from three GEO gene chips (GSE25631, GSE42657 and GSE61710). Then, 1,720 target genes of the 10 miRNAs and 4,185 differently expressed genes in GBM were collected. By intersecting the aforementioned gene clusters, the present study identified 390 overlapping genes. GO and KEGG analyses of the 390 genes demonstrated that these genes were involved in certain cancer­associated biological functions and pathways. Eight genes [(GTPase NRas (NRAS), calcium/calmodulin­dependent protein kinase type II subunit Gamma (CAMK2G), platelet­derived growth factor receptor alpha (PDGFRA), calmodulin 3 (CALM3), cyclin­dependent kinase 6 (CDK6), calcium/calmodulin­dependent protein kinase type II subunit beta (CAMK2B), retinoblastoma­associated protein (RB1) and protein kinase C beta type (PRKCB)] that were centralized in the glioma pathway were selected for CMap analysis. Three chemicals (W­13, gefitinib and exemestane) were identified as putative therapeutic agents for GBM. In summary, the present study identified three miRNA­based chemicals for use as a therapy for GBM. However, more experimental data are needed to verify the therapeutic properties of these latent drugs in GBM.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas/métodos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , Androstadienos/química , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Biologia Computacional , Gefitinibe/química , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Transcriptoma/genética
13.
J Enzyme Inhib Med Chem ; 34(1): 203-217, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30835140

RESUMO

A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 µM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Drogas , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe/química , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
14.
Medicine (Baltimore) ; 98(13): e14135, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921175

RESUMO

BACKGROUND: Combination therapy based on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an emerging trend in cancer treatment, but the clinical value of EGFR-TKIs combination therapy remains controversial. Thus, we conducted a comprehensive analysis of randomized controlled trials (RCTs) comparing EGFR-TKIs combination therapies with monotherapies, aiming to evaluate the safety and efficacy of EGFR-TKIs based combination therapy and to find a more beneficial combination strategy. METHODS: We searched for clinical studies that evaluated EGFR-TKIs combination therapy in cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR) and grade 3/4 treatment-related adverse events (AEs), the hazard ratios (HRs) of overall survival (OS), and progression-free survival (PFS). RESULTS: Fourteen RCTs were identified (n = 3774). Treatments included combinations of EGFR-TKIs and chemotherapy, combinations of EGFR-TKIs and radiotherapy, and combinations of EGFR-TKIs and bevacizumab. EGFR-TKIs combination therapies showed higher ORR [RR: 1.62; 95% confidence interval (95% CI):1.16-2.26; P = .005], PFS (HR: 0.76; 95% CI: 0.64-0.89; P = .001), and OS (HR: 0.88; 95% CI: 0.79-0.97; P = .013) values than monotherapies. However, higher grade 3/4 treatment-related AEs (RR: 1.79; 95% CI: 1.02-3.15; P = .000) were observed in combination therapy than in monotherapy. CONCLUSION: Our pooled analysis and subgroup analysis results showed that the addition of chemotherapy to EGFR-TKIs better benefits PFS and safety. Adding bevacizumab was associated with better ORR and OS. The efficacy and safety of a bevacizumab-EGFR-TKIs-chemotherapy combination should be investigated further.


Assuntos
Bevacizumab/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Intervalo Livre de Doença , Tratamento Farmacológico/métodos , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Gefitinibe/administração & dosagem , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Radioterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Life Sci ; 224: 23-32, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902544

RESUMO

AIMS: The relationship between TRIM59 and drug resistance is elusive despite of its multiple uncovered roles in human cancers. Here we aimed to characterize the expression status of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells and elucidate its mechanism underlying the drug resistance. MAIN METHODS: Gefitinib-resistant cell lines were established by progressive dosage. Relative expression of TRIM59 was determined by both real-time PCR and Western blot. Target gene knockdown was achieved by specific shRNAs. Cell viability was measured by MTT assay. Cell apoptosis was analyzed by flow cytometry with Annexin V/7-AAD double staining. Cell proliferation was determined by clonogenic formation assay. Migration and invasion capacities were detected using transwell chamber assay. Direct interaction between TRIM59 and STAT3 was analyzed by co-immunoprecipitation assay. KEY FINDINGS: We first observed overexpression of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells. ShRNA-mediated knockdown of TRIM59 significantly inhibited cell viability and stimulated apoptosis. Meanwhile, TRIM59-deficiency suppressed cell migration and invasion. We further identified the interaction between TRIM59 and STAT3. TRIM59-deficiency remarkably impaired the activation of STAT3 signaling. STAT3-specific shRNAs significantly re-sensitized TRIM59-proficient EGFR mutant lung adenocarcinoma cells to gefitinib. SIGNIFICANCE: Our data characterized aberrant TRIM59 overexpression in gefitinib-resistance EGFR mutant lung adenocarcinoma cells, and indicated the potential involvement of TRIM59-STAT3 signaling in the occurrence of gefitinib-resistance.


Assuntos
Adenocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Metaloproteínas/metabolismo , Mutação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/genética , Metaloproteínas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
16.
Mol Med Rep ; 19(4): 3230-3236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816529

RESUMO

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR­TKI) is an excellent therapeutic agent to treat EGFR mutation­positive non­small cell lung cancer (NSCLC). However, the initial response decreases as chemoresistance develops. In the present study, gefitinib­resistant EGFR mutant NSCLC PC­9/GR cells were established to examine the characteristics and mechanisms associated with chemoresistance. Axl expression in PC­9/GR cells was transcriptionally upregulated, since Axl protein and mRNA expression levels were identified to be increased according to western blot analysis and reverse transcription polymerase chain reaction results. The inhibitory effect of celastrol on Axl protein expression level, cell viability and clonogenicity were identified in parental and gefitinib­resistant PC­9 cells. In addition, treatment of PC­9/GR cells with celastrol and gefitinib in combination was demonstrated to synergistically suppress Axl protein expression level, cell proliferation and migration. Taken together, upregulation of Axl expression seems to be associated with chemoresistance of PC­9/GR cells. Furthermore, celastrol targets Axl to exert its anticancer effects in order to increase the susceptibility of PC­9/GR cells to gefitinib and overcome chemoresistance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Gefitinibe/farmacologia , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triterpenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética
17.
Mol Pharmacol ; 95(5): 528-536, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858165

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with α isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ERBB target selectivity between afatinib and gefitinib; despite effectively disrupting ERBB2 phosphorylation, the addition of ERBB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual therapy. Accordingly, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. Therefore, our results suggest that the ERBB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ERBB and PI3K combination therapies.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Afatinib/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Piridinas/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Sulfonamidas/farmacologia
18.
Colloids Surf B Biointerfaces ; 177: 425-432, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30798063

RESUMO

In this study, a new type of biodegradable and stable carboxymethyl chitosan (CCS)-enveloped Pluronic® F68/poly(lactic-co-glycolic acid) (PF/PLGA) nanoparticle (CCS/PF/PLGA NP) was developed, and its potential as an oral delivery vehicle to achieve pH-triggered prolonged release, enhance cellular uptake, and promote oral absorption of poorly soluble antitumor compounds was systemically studied. In this nanocarrier, a PF/PLGA NP serves as the core for effective loading, transport, and prolonged release of a chemotherapeutic agent, while a CCS surface layer acts as the shell and provides pH-responsive and mucoadhesive features. Gefitinib (GEF), an oral poorly soluble chemotherapeutic agent, was selected as the model compound. The prepared GEF-loaded CCS/PF/PLGA (GEF/CCS/PF/PLGA) NPs possessed a monodispersed spherical shape with a uniform size (242 ± 6 nm). Thermal analysis confirmed that GEF/CCS/PF/PLGA NPs were present in an amorphous form. Drug release tests showed that GEF/CCS/PF/PLGA NPs have a pH-responsive prolonged release manner with limited drug release at low gastric pH. Furthermore, the mucoadhesive property, intestinal distribution, cellular uptake, and cytotoxicity of CCS/PF/PLGA NPs were also tested. After oral administration in rats, pharmacokinetic analysis revealed that GEF/CCS/PF/PLGA NPs produced approximately 1.6-fold increased bioavailability of GEF when compared to the commercial trademarked product (Iressa®). In addition, under accelerated stability conditions, the prepared GEF/CCS/PF/PLGA NPs exhibited excellent physicochemical stability. Our results suggest that CCS/PF/PLGA NPs exhibit great potential as an effective and stable oral delivery system for achieving pH-triggered sustained release, enhanced cellular uptake, and improved oral absorption of poorly soluble chemotherapeutic agents, such as GEF.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Quitosana/análogos & derivados , Sistemas de Liberação de Medicamentos , Gefitinibe/administração & dosagem , Gefitinibe/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Administração Oral , Antineoplásicos/química , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Gefitinibe/química , Humanos , Tamanho da Partícula , Propriedades de Superfície
19.
Molecules ; 24(3)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759826

RESUMO

Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Lisossomos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autoantígenos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Lisossomos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
J Exp Clin Cancer Res ; 38(1): 96, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791926

RESUMO

BACKGROUND: Drug resistance is common in cancer chemotherapy. This study investigates the role of Glycerol kinase 5 (GK5) in mediating gefitinib resistance in NSCLC. METHODS: The exosomal mRNA of GK5 was detected using a tethered cationic lipoplex nanoparticle (TCLN) biochip. Real-time PCR and Western blot were used to examine the expression of GK5 mRNA and protein in gefitinib-sensitive and -resistant human lung adenocarcinoma cells. The cell counting kit-8, EdU assay, flow cytometry, and JC-1 dye were used to measure cell proliferation, cell cycle, and the mitochondrial membrane potential. RESULTS: We found that the exosomal mRNA of GK5 in the plasma of patients with gefitinib-resistant adenocarcinoma was significantly higher compared with that of gefitinib-sensitive patients. The mRNA and protein levels of GK5 were significantly upregulated in gefitinib-resistant human lung adenocarcinoma PC9R and H1975 cells compared with gefitinib-sensitive PC9 cells. Silencing GK5 in PC9R cells induced mitochondrial damage, caspase activation, cell cycle arrest, and apoptosis via SREBP1/SCD1 signaling pathway. CONCLUSIONS: We demonstrated that GK5 confers gefitinib resistance in lung cancer by inhibiting apoptosis and cell cycle arrest. GK5 could be a novel therapeutic target for treatment of NSCLC with resistance to EGFR tyrosine kinase inhibitors.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Glicerol Quinase/genética , Transdução de Sinais/genética , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/dietoterapia , Adenocarcinoma de Pulmão/genética , Animais , Antineoplásicos/farmacologia , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , RNA Mensageiro/genética , Regulação para Cima/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA