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1.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
J Cancer Res Clin Oncol ; 145(10): 2413-2422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492983

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. METHODS: The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. CONCLUSIONS: PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.


Assuntos
Biomarcadores Tumorais , Neoplasias/etiologia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Especificidade de Órgãos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Anticancer Res ; 39(9): 4817-4828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519584

RESUMO

BACKGROUND/AIM: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. MATERIALS AND METHODS: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. RESULTS: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. CONCLUSION: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Survivina/genética , Tiofenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 39(9): 4829-4835, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519585

RESUMO

BACKGROUND/AIM: Chronic lymphocytic leukemia (CLL) still remains an incurable disease as the cells evade apoptosis, which is an obstacle for current therapeutic approaches. Therefore, our aim was to identify an ideal target of leukemic cell growth for developing inhibitors. MATERIALS AND METHODS: Mouse lymphocytic leukemia cell line L1210, human Toledo cells and a DBA/2 mouse graft model were used to analyze the activity of dual mTORC1/2 inhibitor AZD2014s. Western blotting and flow cytometry were performed to determine the mechanism. RESULTS: AZD2014 inhibited L1210 and human Toledo cell proliferation. Treatment with AZD2014 reduced the phosphorylation levels of S6K1 and 4EBP1 and the protein levels of Rictor, a component of the mTORC2 pathway. AZD2014 induced cell cycle arrest at the G0-G1 phase by reducing the expression of cyclin D1 and CDK4. Oral administration of AZD2014 significantly inhibited the growth of L1210 cell grafts in DBA/2 mice. CONCLUSION: The mTORC1/2 inhibitor may be a better therapeutic agent compared to PI3K/mTORC1 inhibitors for treating patients with CLL.


Assuntos
Antineoplásicos/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patologia , Masculino , Camundongos , Morfolinas/farmacologia
5.
Life Sci ; 234: 116742, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401315

RESUMO

AIMS: The M3 muscarinic acetylcholine receptor (M3R) is a G protein-coupled receptor that is expressed in cases of non-small cell lung cancer (NSCLC). Previous studies demonstrated that M3R antagonists reduce the proliferation of NSCLC. However, how antagonists inhibit the NSCLC proliferation and migration is still little known. This study aims to investigate the mechanism of M3R involved in the growth of NSCLC. MAIN METHODS: The CRISPR/Cas9 was used to knock out (KO) the M3R gene. A real-time cell analyzer (RTCA) was used to record the proliferation of NSCLC cells. The migration and cell cycle of NSCLC cells were evaluated with scratch test and flow cytometry (FCM), respectively. Antibody microarray analysis was performed to detect the expression of proteins after antagonizing M3R and knocking out of M3R, subsequently some of these important proteins were verified by western blot. KEY FINDINGS: The proliferation and migration of NSCLC cells were inhibited by M3R antagonist R2-8018 and knocking out of M3R. Antagonism or knocking out of M3R reduced the phosphorylation of EGFR. Moreover, c-Src and ß-arrestin-1 are involved in the mechanism of how the inhibition of M3R affects EGFR in NSCLC. Further study demonstrated that PI3K/AKT and MEK/ERK signal pathways are involved in M3R-induced EGFR transactivation in NSCLC, and the molecules involved in the cell cycle progression and migration of NSCLC cells were identified. SIGNIFICANCE: This further understanding of the relationship between M3R and NSCLC facilitates the design of therapeutic strategy with M3R antagonist as an adjuvant drug for NSCLC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Receptor Muscarínico M3/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Muscarínico M3/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Expert Rev Clin Pharmacol ; 12(9): 841-849, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31454267

RESUMO

Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML. Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research. Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Recidiva , Sobrevida , Tirosina Quinase 3 Semelhante a fms/genética
7.
Expert Opin Ther Pat ; 29(9): 675-688, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31370713

RESUMO

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Quinases raf/antagonistas & inibidores , Animais , Desenvolvimento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Patentes como Assunto , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases raf/metabolismo
8.
J Enzyme Inhib Med Chem ; 34(1): 1314-1320, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307243

RESUMO

BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have been discovered to be very effective melanoma drugs, but they are known to cause the BRAF paradox. Recently, it was shown that this paradox is caused by the heterodimer phenomenon of BRAF/CRAF. Here, we suggest one method by which paradoxical activation can be avoided by selectively inhibiting BRAFV600E and CRAF but not wild-type BRAF. From previous report of N-(3-(3-alkyl-1H-pyrazol-5-yl) phenyl) aryl amide as a selective inhibitor of BRAFV600E and CRAF, we present compounds that offer enhanced selectivity and efficacy with the aid of molecular modelling.


Assuntos
Projeto Auxiliado por Computador , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 34(1): 1347-1367, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31322015

RESUMO

In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 µM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 µM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Chem Biol Interact ; 310: 108731, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265827

RESUMO

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose/efeitos dos fármacos , Fosforilcolina/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sinergismo Farmacológico , Humanos , Lisofosfolipídeos/análise , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/análise
11.
Expert Opin Ther Pat ; 29(8): 595-603, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31280615

RESUMO

Introduction: As a key element in arguably the most important pathway MAPK signaling, the BRAF kinase gives rise to severe diseases including cancers when pathologically activated. Extensive research on BRAFi (BRAF inhibitor) has been carried out to profile the characters for optimized agents and to elaborate the therapeutic strategies for the related cancer treatment. Areas covered: This review gives an overview of recently approved BRAF agents on function mode, therapeutic efficacy, and deficiency, based on which current challenges and corresponding strategies were presented. New entities as BRAFi for medical purpose in patent literature during the period 2013-2018 were also briefly introduced. Expert opinion: With the disclosure of paradox-breaker BRAFi PLX7904 crystal in complex with BRAF, the rational design for next-generation BRAFi is becoming ever more feasible. Accompanying therapeutic strategies in BRAFi elaboration may also provide flexible choice in the future 'personal medicine'. Further digging in the greatly enriched BRAFi pool will greatly benefit the drug design processes such as FBDD- and SBDD-driven development.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sulfonamidas/farmacologia
12.
Anticancer Res ; 39(7): 3531-3542, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262877

RESUMO

BACKGROUND/AIM: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells. MATERIALS AND METHODS: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes. RESULTS: The synergistic effect was correlated with the increase of annexin V-binding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant. CONCLUSION: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2-mediated phosphorylation of DHFR inside cells.


Assuntos
Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Metotrexato/farmacologia , Naftiridinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Tetra-Hidrofolato Desidrogenase/metabolismo
13.
Anticancer Res ; 39(7): 3579-3584, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262882

RESUMO

BACKGROUND/AIM: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. MATERIALS AND METHODS: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. RESULTS: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. CONCLUSION: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vorinostat/farmacologia , Quinase do Linfoma Anaplásico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
14.
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
15.
Anticancer Res ; 39(7): 3803-3808, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262907

RESUMO

BACKGROUND: Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin. MATERIALS AND METHODS: Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment. RESULTS: SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION: Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Imidazóis/farmacologia , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3
16.
Anticancer Res ; 39(7): 3823-3833, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262910

RESUMO

BACKGROUND/AIM: AKT, also known as protein kinase B (PKB), is an established therapeutic target in cancer and its inhibitors are increasingly designed. The anti-cancer potential of a compound class naphthoquinones has been constantly realized. The current work aimed to explore AKT1 inhibitors from 1,4-naphthoquionone derivatives. MATERIALS AND METHODS: A library of 1,4-naphthoquionone derivatives was formed using similarity search and visual analysis. The library was used for virtual screening using molecular docking. For the screened compounds, the detailed binding pose analysis, binding energy and dissociation constant calculations were performed. RESULTS: The top 10 screened compounds were proposed as potential AKT1 inhibitors with anti-cancer activity. The compounds were checked for any reported activity, and our 2nd rank compound was reported to have anti-cancer activity. CONCLUSION: Our study proposes 10 compounds as potential AKT1 inhibitors and anticancer agents and also provides insights into their binding. This study also proposes AKT1 as a potential target of the reported anticancer compound, CID: 341807.


Assuntos
Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
18.
J Cancer Res Clin Oncol ; 145(10): 2555-2564, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350622

RESUMO

PURPOSE: Previously, the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab (BEV) was investigated. A subgroup analysis of the IMpower150 trial, which investigated the combination of atezolizumab, carboplatin, paclitaxel, and bevacizumab (ABCP), demonstrated the benefit of ABCP in patients harboring EGFR mutations. This study aims to assess the prognostic significance of the qualification for BEV use and the proportion of patients who potentially benefit from BEV-containing combination therapy before and after initial EGFR-TKI treatment. METHODS: We retrospectively analyzed the data of 297 patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations who had received EGFR-TKIs. We performed statistical analyses using the Kaplan-Meier method and the Cox regression adjusted for risk factors. RESULTS: Of the 297 patients, 203 (68%) were eligible to receive BEV ("BEV fit") at the time of EGFR-TKI initiation. Among the "BEV unfit" patients at baseline (n = 70), 14 (20%) became eligible to receive ABCP ("ABCP fit") at the time of EGFR-TKI failure. The median overall survival (OS) of the "BEV fit" and "BEV unfit" patients was 26.2 [95% confidence interval (CI) 23.7-31.2] and 19.1 (95% CI 15.0-25.1) months, respectively (P < 0.001). The multivariate analysis revealed a marked correlation between survival and the qualification for BEV use. CONCLUSIONS: The qualification for BEV use at baseline is independently related to the OS. Some patients harboring EGFR mutations, including those who were "BEV unfit" at baseline, could be eligible for the ABCP regimen after EGFR-TKI treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
19.
Medicine (Baltimore) ; 98(29): e16427, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335695

RESUMO

BACKGROUND: Preclinical in vitro experiments demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) might have synergistic effect in combination with radiotherapy on Non-small cell lung cancer (NSCLC), but the clinical trials showed inconsistence results in NSCLC patients with EGFR status unknow or mutations. This study aimed to determine if added TKIs to Thoracic radiotherapy (TRT) improve primary disease response rate (RR) and survival outcomes in advanced or metastatic NSCLC. METHODS: We searched MEDLINE, EMBASE, and Cochrane Library from January 2000 to December 2017 for eligible studies where patients received concurrent EGFR TKIs and TRT or CRT. Concerned outcomes were primary tumor RR, overall survival (OS), and adverse events (AEs). The meta-analysis was performed using Stata software (version 12.0). Random effects models were used to pool outcomes across studies. Sensitivity analysis was performed to determine if the results would be different. RESULTS: We found 16 prospective clinical trials with mature results for meta-analyses. Twelve studies including 446 patients reported the RR and survival outcomes of TRT combined TKIs. The CR, PR, SD, and PD, respectively, were 0.06 (95% CI 0.03-0.09, I = 0%), 0.44 (95% CI 0.38-0.49, I = 64.9%), 0.29 (95% CI 0.24-0.34, I = 78.4%), and 0.15 (95% CI 0.11-0.19, I = 84.2%). One- and 2-year OS, respectively, were 0.52 (95% CI 0.44-0.60, I = 38.8%) and 0.26 (95% CI 0.18-0.33, I = 0%). Four studies including 182 patients reported the RR and survival outcomes of CRT combined TKIs. The pooled CR, PR, SD, and PD, respectively, were 0.12 (95% CI 0.02-0.22, I = 69.1%), 0.41 (95% CI 0.27-0.55, I71.6%), 0.31 (95% CI 0.16-0.46, I = 79%), and 0.14 (95% CI -0.01-0.30, I = 87.8%). Only 1 study reported the survival event rate, 1- and 2-year OS, respectively, were 0.83 (95% CI 0.71-0.94) and 0.67 (95% CI 0.54-0.81). There were not severe adverse events (SAEs) reported either TRT combined TKIs or CRT combined TKIs. CONCLUSION: There is evidence, albeit of low quality, that added the TKIs to TRT or CRT may improve RR and survival outcomes in patients with EGFR mutant status unknown advanced or metastatic NSCLC relative to other studies of TKIs alone, TRT alone or CRT.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia/métodos , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Estadiamento de Neoplasias , Resultado do Tratamento
20.
Curr Top Med Chem ; 19(6): 467-485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31184298

RESUMO

BACKGROUND: Kinases are key modulators in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome. Understanding the interaction of kinases with different substrates and other proteins is vital to decode the cell signaling machinery as well as causative mechanism for disease onset and progression. OBJECTIVE: The objective of this review is to present all studies on the structure and function of few important kinases and highlight the protein-protein interaction (PPI) mechanism of kinases and the kinase specific interactome databases and how such studies could be utilized to develop anticancer drugs. METHODS: The article is a review of the detailed description of the various domains in kinases that are involved in protein-protein interactions and specific inhibitors developed targeting these PPI domains. RESULTS: The review has surfaced in depth the interacting domains in key kinases and their features and the roles of PPI in the human kinome and the various signaling cascades that are involved in certain types of cancer. CONCLUSION: The insight availed into the mechanism of existing peptide inhibitors and peptidomimetics against kinases will pave way for the design and generation of domain specific peptide inhibitors with better productivity and efficiency and the various software and servers available can be of great use for the identification and analysis of protein-protein interactions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Mapeamento de Interação de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Antineoplásicos/química , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Peptidomiméticos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/química
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