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1.
Drugs ; 79(12): 1287-1304, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313099

RESUMO

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Aprovação de Drogas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Terapia de Alvo Molecular , Nitrofenóis/uso terapêutico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
2.
Curr Top Med Chem ; 19(13): 1162-1172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210110

RESUMO

BACKGROUND: Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately. OBJECTIVE: In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2). METHODS: We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching. RESULTS: We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds. CONCLUSION: Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.


Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Algoritmos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
3.
Nat Commun ; 10(1): 2385, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160589

RESUMO

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.


Assuntos
Antineoplásicos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/metabolismo , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cristalização , Cristalografia por Raios X , Humanos , Mutação , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Ressonância de Plasmônio de Superfície
4.
Expert Opin Ther Pat ; 29(7): 487-496, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31154862

RESUMO

INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies. AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations, in vitro and in vivo efficacy as well as the therapeutic application of venetoclax. EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Patentes como Assunto , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia
5.
Chem Biol Interact ; 309: 108723, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228469

RESUMO

Ischemic preconditioning and pharmacological preconditioning are common strategies to prevent lethal myocardial injury, especially nutritional preconditioning (NPC). In this study, we investigated the effects of astragaloside IV (Ast), as an NPC agent, on myocardium suffered anoxia/reoxygenation (A/R) injury. Rats received 5 mg/kg Ast daily for 3 weeks by intragastric administration. Then, hearts were harvested and underwent A/R treatment using a Langendorff apparatus. Ast- pretreatment significantly promoted functional recovery of the myocardium, reduced infarct size, and oxidative stress, and decreased the apoptotic index. Similar findings were demonstrated in H9c2 cardiomyocytes that were pretreated with Ast for 24 h. Moreover, Ast-pretreatment significantly upregulated Bcl-2 expression, especially in mitochondria. The effects of Ast treatment against A/R injury were also reflected by increased antioxidant potential, inhibited reactive oxygen species (ROS) burst, increased oxygen consumption rate, maintained mitochondrial membrane potential (MMP), inhibited mitochondrial permeability transition pore (mPTP) opening, and prevented apoptosis. Selective inhibition of Bcl-2 by ABT-737 decreased myocardial injury protection of Ast. Ast-pretreatment resulted in NPC- related effects against A/R, and mitochondria may be the target of a cascade of events elicited by upregulating Bcl-2 expression, promoting translocation of Bcl-2 into mitochondria, maintaining MMP, inhibiting ROS bursts, thereby leading to recovery of mitochondrial respiration, preventing mPTP opening, decreasing cytochrome C release, preventing apoptosis, and ultimately alleviating myocardial injury.


Assuntos
Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo
6.
Eur J Med Chem ; 177: 63-75, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129454

RESUMO

A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/química
7.
Mol Med Rep ; 19(6): 5251-5262, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059100

RESUMO

Keloids are benign fibrous overgrowths that occur as a result of abnormal wound healing following cutaneous injury. MicroRNAs (miRNAs/miRs) are short non­coding RNAs that serve critical roles in numerous important biological processes, such as cell proliferation, differentiation and apoptosis. However, their role in keloid development remains largely unknown. In the present study, the role of miR­30a­5p, a miRNA regulated by Trichostatin A (TSA), in apoptosis within cultured keloid fibroblasts was investigated. An MTT assay was used to detect the proliferation of cultured keloid fibroblasts treated with TSA. Cell apoptosis and cell cycle phases were analyzed using flow cytometry. In addition, an miRNA microarray was performed to compare expression profiles between cultured keloid fibroblasts treated with or without 1,000 nM TSA. Reverse transcription­quantitative polymerase chain reaction analysis was conducted to estimate miRNA expression levels. The direct target of miR­30a­5p was identified using a dual­luciferase reporter assay. Western blotting was employed to assess protein expression levels in keloid fibroblasts. The results demonstrated that TSA inhibited the proliferation of keloid fibroblasts in a time­ and dose­dependent manner. The miRNA microarray revealed alterations in the expression of numerous miRNA sequences in response to TSA when compared with controls. Notably, the expression of miR­30a­5p was downregulated in keloid tissues. In addition, overexpression of miR­30a­5p induced apoptosis by targeting B­cell lymphoma 2, which was similar to that observed in response to TSA. These results provide important information regarding a novel miR­30a­5p­mediated signaling pathway induced by TSA treatment, and suggest a potential use for TSA and miR­30a­5p as effective therapeutic strategies for keloids.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Análise por Conglomerados , Colágeno/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Queloide/metabolismo , Queloide/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Pele/metabolismo , Pele/patologia
8.
Expert Opin Drug Metab Toxicol ; 15(5): 353-366, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30969139

RESUMO

INTRODUCTION: Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Rituximab/administração & dosagem , Sulfonamidas/farmacologia
9.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986908

RESUMO

The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-N-arylhydrazine-1-carbothioamide (5a-b) intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound 6i) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC50 activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of 6i was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolinas/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Oxidiazóis/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Triazóis/uso terapêutico
10.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018543

RESUMO

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease have led to the identification of novel therapeutic targets. In the last two years, seven new targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, glasdegib, venetoclax and gemtuzumab ozogamicin) have received US Food and Drug Administration (FDA) approval for the treatment of AML. These drugs did not just prove to have a clinical benefit as single agents but have especially improved AML patient outcomes if they are combined with conventional therapy. In this review, we will focus on currently approved and promising upcoming agents and we will discuss controversial aspects and limitations of targeted treatment strategies.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Imunoconjugados/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Animais , Aprovação de Drogas , Desenvolvimento de Medicamentos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo
12.
Curr Top Med Chem ; 19(6): 457-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836917

RESUMO

BACKGROUND: Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects. OBJECTIVE: In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer. METHODS: Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs. RESULTS: The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges. CONCLUSION: Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.


Assuntos
Aminoácidos/genética , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Aminoácidos/metabolismo , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Estrutura Molecular , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas/química
13.
BMC Cancer ; 19(1): 243, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885150

RESUMO

BACKGROUND: High-risk neuroblastoma with N-Myc amplification remains a therapeutic challenge in paediatric oncology. Antagonism of pro-death Bcl-2 homology (BH) proteins to pro-survival BH members such as Mcl-1 and Bcl-2 has become a treatment approach, but previous studies suggest that a combined inhibition of Bcl-2 and Mcl-1 is necessary. TW-37 inhibits Mcl-1 and Bcl-2 with almost the same affinity. However, single-agent cytotoxicity of TW-37 in neuroblastoma cell lines has not been investigated. METHODS: Cell viability, apoptosis, proliferation and changes in growth properties were determined in SKNAS, IMR-5, SY5Y and Kelly cells after treatment with TW-37. After transfection with Mcl-1 or Bcl-2 siRNA, apoptosis and proliferation were investigated in Kelly cells. Mice with Kelly cell line xenografts were treated with TW-37 and tumor growth, survival and apoptosis were determined. RESULTS: Cell lines with N-Myc amplification were more sensitive to TW-37 treatment, IC50 values for IMR-5 and Kelly cells being 0.28 µM and 0.22 µM, compared to SY5Y cells and SKNAS cells (IC50 0.96 µM and 0.83 µM). Treatment with TW-37 resulted in increased apoptosis and reduced proliferation rates, especially in IMR5 and Kelly cells. Bcl-2 as well as Mcl-1 knockdown induced apoptosis in Kelly cells. TW-37 led to a decrease in tumor growth and a favorable survival (p = 0.0379) in a Kelly neuroblastoma xenografts mouse model. CONCLUSION: TW-37 has strong single-agent cytotoxicity in vitro and in vivo. Therefore, combined inhibition of Bcl-2/Mcl-1 by TW-37 in N-Myc amplified neuroblastoma may represent an interesting therapeutic strategy.


Assuntos
Benzamidas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Amplificação de Genes , Técnicas de Silenciamento de Genes , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonas/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
PLoS One ; 14(1): e0210859, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682083

RESUMO

BACKGROUND: Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. MATERIALS AND METHODS: We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. RESULTS: Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. CONCLUSION: A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Mutações Sintéticas Letais/efeitos dos fármacos , Bevacizumab/administração & dosagem , Ensaios Clínicos como Assunto , Feminino , Humanos , Paclitaxel/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética
15.
Med Sci Monit ; 25: 730-738, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30681073

RESUMO

BACKGROUND Berberine, a natural isoquinoline alkaloid derived from Berberis genus plants, has been reported to have anti-cancer effects. While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs in progression and berberine effects on colorectal cancer are largely unknown. Therefore, the present study investigated the involvement and regulatory function of lncRNA cancer susceptibility candidate 2 (CASC2) during the treatment of human colorectal cancer using berberine. MATERIAL AND METHODS Reverse transcription-quantitative PCR (RT-qPCR) was performed to detect the expression levels of lncRNA CASC2 and Bcl-2 mRNA in colorectal cancer cells. MTT assay was performed to evaluate cell viability. Flow cytometry and TUNEL assay were used to analyze the apoptosis of cancer cells. RNA immunoprecipitation (RIP) assay was done to verify the interaction between lncRNA CASC2 and (AU-binding factor 1) AUF1, or AUF1 and B-cell CLL/lymphoma 2 (Bcl-2). RESULTS Treatment with berberine suppressed cell viability of colorectal cancer by promoting apoptosis level. LncRNA CASC2 was upregulated in cells treated with berberine, and knockdown of lncRNA CASC2 reversed the berberine-induced apoptosis. In addition, anti-apoptotic gene Bcl-2 was suppressed by berberine treatment and lncRNA CASC2, inducing the pro-apoptotic effects. Moreover, lncRNA CASC2 binds to AUF1, which sequestered AUF1 from binding to Bcl-2 mRNA, thus inducing the inactivation of Bcl-2 translation. CONCLUSIONS Our study reveals that lncRNA CASC2 mediates the berberine-induced pro-apoptotic effect via inhibition of Bcl-2 expression at the post-transcriptional level.


Assuntos
Berberina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Humanos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
16.
Food Chem Toxicol ; 125: 354-360, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30677442

RESUMO

Ever since several targeted agents were introduced a decade ago, progress in new therapeutic strategies for colorectal cancer (CRC) has been much slower than that for other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is widely known to induce cellular apoptosis in numerous cancer cell types. However, many cancer cells are resistant to the effects of TRAIL, and thus, approaches are needed to overcome TRAIL resistance. We demonstrated that non-cytotoxic doses of diallyl disulfide (DADS) increased TRAIL-associated cell death in CRC cell lines. Additionally, synergistic effects between DADS and TRAIL were validated in vivo in nude mice. One process involved in these effects includes down-regulation of the anti-apoptotic protein Bcl-2, and the synergistic effect of DADS with TRAIL was attenuated in Bcl-2-over-expressing cells. Taken together, the results of this study give new insights into the role of DADS in TRAIL-related repression of CRC progression by inhibition of Bcl-2.


Assuntos
Compostos Alílicos/farmacologia , Apoptose/efeitos dos fármacos , Dissulfetos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Caspases/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
17.
Biomed Pharmacother ; 109: 2192-2202, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551476

RESUMO

Chemotherapy is the main postsurgical and adjuvant therapy for glioma, and intrinsic or acquired temozolomide (TMZ) resistance may result in poor prognosis. The miR-181 family was discovered to play an important role in regulating biological functions in glioma, and miR-181b is less expressed in human gliomas as a tumor-suppressive miRNA. The aim of this study was to explore the molecular mechanism of miR-181b-5p and its target gene on modulating TMZ chemosensitivity in glioma cells. The enhanced chemosensitivity effect of miR-181b-5p to TMZ in glioma cells U87MG and U251 was detected by MTT method. Dual luciferase reporter assay, quantitative real-time PCR (qRT-PCR) and Western blotting were performed to demonstrate that miR-181b-5p directly targets Bcl-2 to reduce the expression. Transwell and flow cytometry assays showed that combination of miR-181b-5p and TMZ exerted stronger effects on inhibiting U87MG cells proliferation, migration and invasion as well as promoting apoptosis and S phase arrest than miR-181b-5p and TMZ alone. The same tendency was observed in the upregulation of apoptosis-related protein Bax and downregulation of cycle-related proteins CyclinD1 and CDK4. In vivo experiments indicated that miR-181b-5p could enhance the tumor-suppressive effect of TMZ. In conclusion, our findings indicate that upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Temozolomida/administração & dosagem , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Glioma/tratamento farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Mar Drugs ; 16(12)2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572618

RESUMO

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1'(R), and 6'(S) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Isoxazóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Tirosina/análogos & derivados , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HL-60 , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/química , Isoxazóis/isolamento & purificação , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Simulação de Acoplamento Molecular , Poríferos/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/administração & dosagem , Tirosina/administração & dosagem , Tirosina/química , Tirosina/isolamento & purificação , Tirosina/farmacologia , Células U937
19.
Nat Commun ; 9(1): 5435, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30575733

RESUMO

Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that Prf1-/- mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and lower survival. Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice. In LMNA+/G609G progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.


Assuntos
Senescência Celular , Imunossenescência , Perforina/fisiologia , Animais , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Inflamação/etiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Progéria/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
20.
Int J Mol Sci ; 19(12)2018 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-30544835

RESUMO

Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Apoptose , Humanos , Modelos Biológicos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
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