Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 552
Filtrar
1.
Medicine (Baltimore) ; 99(5): e18811, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000382

RESUMO

RATIONALE: Concurrent calreticulin (CALR) mutation and BCR-ABL1 fusion are extremely rare in chronic myelogenous leukemia; to date, only 12 cases have been reported. PATIENT CONCERNS: A 57-year-old male who had an 11-year history of essential thrombocytosis presented to our hospital with leukocytosis and marked splenomegaly for 3 months. DIAGNOSES: Chronic myelogenous leukemia with myeloid fibrosis arising on the background of essential thrombocytosis harboring both BCR-ABL1 fusion and type-1 like CALR mutation. INTERVENTIONS: Imatinib was started at 300 mg daily and increased to 400 mg daily after 3 months; interferon was added after 12 months. OUTCOMES: Partial cytogenetic response was achieved after 3 months of imatinib therapy and complete cytogenetic response was achieved after 1 year of treatment. However, CALR mutation was still present with a stable mutational allele burden. LESSONS: In this case report and review of additional 12 cases with simultaneous presence of CALR-mutation and BCR-ABL1 fusion, we highlighted the importance of integrating clinical, morphological, and molecular genetic data for classifying atypical myeloid neoplasms.


Assuntos
Calreticulina/genética , Proteínas de Fusão bcr-abl/genética , Genes abl , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Trombocitemia Essencial/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/antagonistas & inibidores , Trombocitemia Essencial/complicações
2.
Chem Biodivers ; 17(2): e1900659, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31995280

RESUMO

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940's. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2-(2-bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4-oxadiazole derivatives 4a-4j have been synthesized and described by spectroscopic method. 2-(2-Bromo-6-nitrophenyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (4c) was reconfirmed by single-crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF-7, MDA-MB-453 and MCF-10A non-cancer cell lines. The compounds with the methoxy (in 4c) and methyl (in 4j) substitution were shown to have significant cytotoxicity, with 4c showing dose-dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein-ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.


Assuntos
Antineoplásicos/síntese química , Desenho de Drogas , Oxidiazóis/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Oxidiazóis/metabolismo , Oxidiazóis/farmacologia , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 185: 111748, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648125

RESUMO

Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPARγ agonists on the ability to circumvent resistance, the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1'-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment. Especially the derivatives 18a-f, which did not activate PPARγ to more than 40% at 10 µM, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Telmisartan/farmacologia , Animais , Antineoplásicos/química , Células COS , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Mesilato de Imatinib/química , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Estrutura Molecular , PPAR gama/agonistas , Relação Estrutura-Atividade , Telmisartan/análogos & derivados , Telmisartan/química
4.
Vet J ; 254: 105398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31836165

RESUMO

Canine lymphoma is one of the most common malignant tumours occurring in dogs and has a high incidence worldwide. Despite advances in cancer prevention, the treatment of neoplastic diseases still requires improvement. Some cancer cells may resist the effect of chemotherapeutic agents by up-regulating drug transporters leading to increased drug efflux, resulting in intrinsic or acquired drug resistance, which is a mechanism commonly seen in doxorubicin-resistant tumour cells. In this study, canine B-cell lymphoma cell line CLBL1-8.0, a doxorubicin-resistant B cell lymphoma cell line derived from CLBL-1 by increasing the doxorubicin concentration during culturing, exhibited high expression of P-glycoprotein (P-gp, ATP-binding cassette sub-family B member 1 [ABCB1]). These proteins are commonly involved in cancer cell resistance to doxorubicin. Imatinib, a tyrosine kinase inhibitor significantly potentiated the sensitivity of doxorubicin in P-gp-overexpressing doxorubicin-resistant cells. Moreover, a combination of these two drugs may increase the retention of doxorubicin by decreasing the efflux of doxorubicin without affecting P-gp protein overexpression. In conclusion, imatinib reversed doxorubicin resistance by decreasing drug efflux in P-gp-overexpressing doxorubicin-resistant canine lymphoma cells. These results suggest that combining doxorubicin, one of the most widely used chemotherapeutic drugs in the treatment of canine lymphoma, with imatinib might potentially overcome doxorubicin resistance in a clinical setting.


Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Doxorrubicina/farmacologia , Mesilato de Imatinib/farmacologia , Linfoma de Células B/veterinária , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Cães , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Linfoma de Células B/tratamento farmacológico
5.
Molecules ; 24(19)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581474

RESUMO

Imatinib is an effective anticancer drug for the treatment of leukemia. Interestingly, when an FDA-approved drug library was tested for agents that block peroxisome proliferator-activated receptor γ (PPARγ) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPARγ antagonist ligand. However, it is not well understood how imatinib binds to PPARγ or would improve insulin sensitivity without classical agonism. Here, we report the crystal structure of the PPARγ R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPARγ, of which the Arm3 region is closely related to the inhibition of PPARγ phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2' and the Ω loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPARγ helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPARγ regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPARγ while minimizing known side effects.


Assuntos
Hipoglicemiantes/farmacologia , Mesilato de Imatinib/farmacologia , PPAR gama/química , PPAR gama/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Mesilato de Imatinib/química , Modelos Moleculares , Mutação , PPAR gama/genética , Fosforilação/efeitos dos fármacos , Domínios Proteicos , Estrutura Secundária de Proteína , Serina/metabolismo
6.
Biomed Pharmacother ; 119: 109413, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518872

RESUMO

MicroRNA-mediated posttranscriptional regulation is an important epigenetic regulatory mechanism of gene expression, and its dysregulation is involved in the development and progression of a variety of malignancies, including chronic myeloid leukemia (CML). The BCR-ABL1 fusion gene is not only the initiating factor of CML, but it is also an important driving factor for blastic transformation. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase activity, represented by imatinib, are currently the first-line treatment for CML. However, due to primary resistance or secondary resistance caused by mutations in the BCR-ABL1 kinase domain, TKIs cannot completely prevent the progression of CML; thus, the study of BCR-ABL1 gene expression regulation is of great significance. In this study, bioinformatics analysis and our results showed that miR-96 could directly bind to the 3'UTR region of BCR-ABL1 to regulate fusion protein expression, thereby regulating its downstream signaling pathway activity. We also found that miR-96 was downregulated during the progression from the chronic phase (CML-CP) to the blast crisis (CML-BC). Downregulation of miR-96 could promote the proliferation and participate in the cell differentiation of CML-BC cells. Additionally, we found that the novel histone deacetylase drug chidamide and the DNA methyltransferase inhibitor decitabine could restore the low expression of miR-96 in CML cells, and there were two abnormal hypermethylated sites in the promoter region of miR-96 in CML, suggesting that its low expression might be at least partially regulated by epigenetic mechanisms. In addition, re-expression of miR-96 could increase the sensitivity of CML-BC cells to imatinib. Thus, miR-96 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in CML blastic transformation.


Assuntos
Crise Blástica/genética , Transformação Celular Neoplásica/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética , Oncogenes , Regiões 3' não Traduzidas/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Sequência de Bases , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Crise Blástica/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Decitabina/farmacologia , Decitabina/uso terapêutico , Regulação para Baixo/genética , Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MicroRNAs/metabolismo , Biossíntese de Proteínas
7.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(9): 886-890, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31550829

RESUMO

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Mesilato de Imatinib/farmacologia
8.
Oxid Med Cell Longev ; 2019: 5813985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396300

RESUMO

Background: The mechanisms of crosstalk between depression and gastric cancer (GC) remain ill defined. Given that reactive oxygen species (ROS) is involved in the pathophysiology of both GC and depression, we try to explore the activities of ROS in the development of GC and GC-related depression. Methods: 110 patients with newly diagnosed GC were recruited in our study. The clinical characteristics of these patients were recorded. Inflammation and oxidative stress markers were detected by ELISA. The depression status of patients with GC was assessed during follow-up. The association between ROS, ABL1, and inflammation factors was evaluated in H2O2-treated GC cell lines and The Cancer Genome Atlas (TCGA) database. The effect of ABL1 on inflammation was detected with Imatinib/Nilotinib-treated GC cell lines. A chronic mild stress- (CMS-) induced patient-derived xenograft (PDX) mice model was established to assess the crosstalk between depression and GC. Results: Depression was correlated with poor prognosis of patients with GC. GC patients with depression were under a high level of oxidative status as well as dysregulated inflammation. In the CMS-induced GC PDX mice model, CMS could facilitate the development of GC. Additionally, tumor bearing could induce depressive-like behaviors of mice. With the treatment of ROS, the activities of ABL1 and inflammatory signaling were enhanced both in vitro and in vivo, and blocking the activities of ABL1 inhibited inflammatory signaling. Conclusions: ROS-activated ABL1 mediates inflammation through regulating NF-κB1 and STAT3, which subsequently leads to the development of GC and GC-related depression.


Assuntos
Depressão/etiologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , /sangue , Animais , Antineoplásicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Depressão/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Nus , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/complicações
9.
Expert Opin Pharmacother ; 20(13): 1539-1550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381378

RESUMO

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.


Assuntos
Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Humanos , Mesilato de Imatinib/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo
10.
Mol Med Rep ; 20(4): 3233-3239, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432109

RESUMO

Homoharringtonine (HHT) and imatinib have a synergistic effect in the clinical treatment of chronic myeloid leukemia (CML). The purpose of the present study was to explore the underlying mechanisms by which HHT enhanced imatinib sensitivity. K562 CML cells were treated with HHT and imatinib separately or in combination. Cell viability was detected by Cell Counting Kit­8 assay; apoptotic rates and protein expression levels of phosphorylated­tyrosine (p­Tyr) and p­CRK like proto­oncogene, adaptor protein (p­Crkl) were analyzed by flow cytometry; zinc­finger protein, X­linked (ZFX) overexpression plasmid was transfected to cells using electroporation; western blotting was used to detect the protein expression levels of PI3K, AKT, p­AKT and ZFX; and reverse transcription­quantitative PCR was used to measure ZFX mRNA expression levels. The results demonstrated that HHT and imatinib co­treatment had significant effects of proliferation inhibition and apoptosis induction on K562 CML cells compared with imatinib alone. Co­treatment also significantly downregulated the expression levels of p­Tyr, p­Crkl, PI3K and p­Akt compared with imatinib or HHT treatment. In addition, HHT downregulated ZFX mRNA and protein expression. ZFX overexpression reversed cell sensitivity to imatinib and HHT and also reduced the HHT­induced imatinib sensitization by increasing p­Akt expression. In conclusion, HHT may enhance the effect of imatinib on CML cells by downregulating ZFX.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Mepesuccinato de Omacetaxina , Mesilato de Imatinib , Fatores de Transcrição Kruppel-Like/biossíntese , Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas de Neoplasias/biossíntese , Apoptose/efeitos dos fármacos , Mepesuccinato de Omacetaxina/agonistas , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Mesilato de Imatinib/agonistas , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
11.
Oncogene ; 38(38): 6550-6565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31363162

RESUMO

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Proteínas I-kappa B/metabolismo , Mesilato de Imatinib/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/fisiologia , Fator de Transcrição RelA/metabolismo , Animais , Células COS , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
Cancer Sci ; 110(10): 3255-3266, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31402561

RESUMO

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative-minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive-MRD with complete remission [CR] and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative-MRD or positive-MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new-generation TKI for high-risk patients are warranted to improve the outcomes after allogeneic HSCT.


Assuntos
Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Terapia Combinada , Dasatinibe/administração & dosagem , Dasatinibe/farmacologia , Feminino , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/farmacologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Indução de Remissão , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
13.
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
14.
Eur J Pharmacol ; 860: 172559, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31325435

RESUMO

Abdominal aortic aneurysm (AAA) is characterized with progressive weakening and considerable dilation of the aortic wall. Despite the high risk of mortality in the elderly population, there are still no clinical pharmacological therapies to alleviate AAA progression. Macrophage-derived MMP9 acts as a key factor in extracellular matrix degradation and is crucial for aortic aneurysm development and aortic rupture. Here, we demonstrated that the transcription level of MMP9 was suppressed with a concentration-dependent manner in macrophages after Imatinib treatment, which was accompanied by the down-regulation of MMP9 protein expression and reduced MMP9 secretion in vitro. Imatinib administration (50 mg/kg/d, i.g.) was carried out one week after the establishment of elastase-induced AAA in rats, stabilizing aneurysm progression and improving survival rate via decreasing the aortic diameter and preventing elastin degradation. Expression and activity of MMP9 in the artery tissues were significantly suppressed after Imatinib treatment via in situ assessment like immunohistochemistry and zymography, although macrophage infiltration was not affected. Furthermore, we found that Imatinib inhibited MMP9 transcription through reduction of STAT3 phosphorylation and translocation from nucleus to cytoplasm. These observations indicated that Imatinib prevents aneurysm progression by inhibiting STAT3-mediated MMP9 expression and activation, suggesting a new application of Imatinib on AAA clinical therapy.


Assuntos
Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/prevenção & controle , Progressão da Doença , Mesilato de Imatinib/farmacologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Elastase Pancreática/efeitos adversos , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Metaloproteinase 9 da Matriz/genética , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo
15.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252559

RESUMO

Since many oncogenes, including BCR-ABL, may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial complex subunits thus causing alterations of glucose metabolism. BCR-ABL-driven K562 and KCL-22 cells were incubated with increasing concentrations of imatinib to preliminarily test drug sensitivity. Then untreated and treated cells were analyzed for levels of BCR-ABL signaling mediators and key proteins of glycolytic cascade and oxidative phosphorylation. Effective inhibition of BCR-ABL caused a concomitant reduction of p-ERK1/2, p-AKT, phosphorylated form of STAT3 (at Tyr705 and Ser727), c-Myc and cyclin D1 along with an increase of cleaved PARP and caspase 3 at 48 h after treatment. Furthermore, a strong reduction of the hexokinase II (HKII), phosphorylated form of PKM2 (at Tyr105 and Ser37) and lactate dehydrogenase A (LDH-A) was observed in response to imatinib along with a strong upregulation of mitochondrial complexes (OXPHOS). According to these findings, a significant reduction of glucose consumption and lactate secretion along with an increase of intracellular ATP levels was observed in response to imatinib. Our findings indicate that imatinib treatment of BCR-ABL-driven human leukemia cells reactivates mitochondrial oxidative phosphorylation thus allowing potential co-targeting of BCR-ABL and OXPHOS.


Assuntos
Antineoplásicos/farmacologia , Glicólise/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Humanos , Ácido Láctico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/metabolismo
16.
Eur J Med Chem ; 178: 232-242, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185413

RESUMO

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-AblWT and Bcr-AblT315I kinases with IC50 of 0.043 µM and 0.17 µM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 µM and 5.42 µM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Mutação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Maleabilidade , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo
17.
Biomed Pharmacother ; 117: 109071, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202171

RESUMO

Philadelphia chromosome-positive (Ph+) is considered as a high risk of acute lymphoblastic leukemia (ALL). Tyrosine kinase inhibitors (TKIs) are tailored drug for Ph+ ALL, but Ik6 is associated with TKI resistance and poor outcome of Ph+ ALL. In the present study, we investigated the potential benefit of combination therapy with imatinib and Huaier extract, a traditional Chinese medicine, in Ik6+ Ph+ ALL. The Ik6+ Ph+ -ALL cell lines Sup-B15 or BV173 were treated with Huaier extract, imatinib or the combination of the two. Analysis of cell proliferation showed that the combined treatment of imatinib and Huaier extract exhibited a greater effect on cell inhibition. Using flow cytometry and Western blot, enhanced effects on the induction of cell apoptosis were observed. The combination of the two drugs also exhibited a significant effect in decreasing the protein and enzymatic activity levels of BCR-ABL. The molecular mechanisms may be involved in BCR-ABL related pathways, including the inactivation of p-AKT, p-STAT5, p-mTOR and p-Lyn. Consistent with the in vitro results, the combination of Huaier extract and imatinib inhibit the growth and infiltration of xenografted tumors. Taken together, our findings show that Huaier extract enhances the anticancer efficacy of imatinib in Ik6+ Ph+ ALL Further, it also provides a potential clinical application in the treatment of refractory Ph+ ALL.


Assuntos
Misturas Complexas/química , Fator de Transcrição Ikaros/metabolismo , Mesilato de Imatinib/uso terapêutico , Cromossomo Filadélfia , Extratos Vegetais/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
18.
Braz J Med Biol Res ; 52(6): e8399, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166382

RESUMO

Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , RNA Longo não Codificante/genética , Receptores de Somatomedina/genética , Apoptose , Linhagem Celular Tumoral , Regulação para Baixo/genética , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , RNA Longo não Codificante/metabolismo , Receptores de Somatomedina/metabolismo , Transdução de Sinais
19.
Oncol Rep ; 42(2): 571-580, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233186

RESUMO

Imatinib­based targeted treatment is the standard therapy for chronic myeloid leukemia (CML); however, drug resistance is an inevitable issue for imatinib­based CML treatment. Imatinib resistance can be ascribed to Bcr­Abl­dependent and independent resistance. In the present study, peripheral blood samples were collected from imatinib­sensitive (IS) and imatinib­resistant (IR) CML patients and transcriptome sequencing was carried out. From the RNA­seq data, a significantly altered IR­related gene (IRG), ribonucleotide reductase regulatory subunit M2 (RRM2) was identified. Using real­time quantitative fluorescence PCR (qF­PCR), we found that RRM2 was elevated in both IR CML patients and an IR cell line. Using reverse­transcription PCR (RT­PCR) and western blot analysis, we indicated that imatinib can increase RRM2 level in a dose­dependent manner in IR cells. We also demonstrated that RRM2 is involved in the Bcl­2/caspase cell apoptotic pathway and in the Akt cell signaling pathway, and therefore affects the cell survival following imatinib therapy. The present study, for the first time, indicates that RRM2 is responsible for drug resistance in imatinib­based therapy. Therefore, RRM2 gene can be considered as a potential therapeutic target in the clinical treatment of CML.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Ribonucleosídeo Difosfato Redutase/antagonistas & inibidores , Adolescente , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Células Tumorais Cultivadas , Adulto Jovem
20.
Reprod Biol ; 19(2): 133-138, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31080158

RESUMO

Chemotherapy may result in ovarian atrophy, a depletion of the primordial follicle pool, diminished ovarian weight, cortical and stromal fibrosis. Imatinib mesylate is an anticancer agent that inhibits competitively several receptor tyrosine kinases (RTKs). RTKs play important roles in cell metabolism, proliferation, and apoptosis. In clinic, imatinib mesylate is also known as an anti-fibrotic medicine. In the present study, the impact of imatinib on the ovarian tissue was investigated by assessing ovarian tissue fibrosis in postnatal rat administered with or without imatinib for three days. Fibrosis in the ovarian tissue was determined by histology (Picrosirius and Masson's trichrome staining) and the protein expression of vimentin and alpha-smooth muscle actin (α-SMA). Furthermore, mRNA expression of Forkhead box transcription factor O1 and O3 (FOXO1 and FOXO3), which are markers of cell proliferation was quantified. A short-term exposure to imatinib showed to increase tissue fibrosis in ovaries. This was observed by Masson's trichrome staining. Exposure to imatinib led also to a down-regulation of vimentin protein expression and up-regulation mRNA expression of FOXO3. This may indicate a role of FOXO3 in ovarian tissue fibrosis in postnatal rat ovaries.


Assuntos
Fibrose/tratamento farmacológico , Mesilato de Imatinib/farmacologia , Doenças Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Actinas/genética , Actinas/metabolismo , Animais , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Vimentina/genética , Vimentina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA