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1.
Nat Commun ; 11(1): 259, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937780

RESUMO

A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.


Assuntos
Antimitóticos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proteínas de Membrana/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular , Feminino , Técnicas de Inativação de Genes , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Proteínas de Membrana/genética , Camundongos , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo
2.
Immunity ; 52(1): 96-108.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31810881

RESUMO

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl4) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl4-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/metabolismo , Interferon gama/imunologia , Fígado/citologia , Linfócitos/imunologia , Proteína bcl-X/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Feminino , Subunidade p35 da Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/lesões , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Biochim Biophys Acta Gene Regul Mech ; 1863(1): 194475, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870784

RESUMO

Targeting the apoptosis machinery is a promising therapeutic approach in myeloid malignancies. BCL2L1 is a well-known glucocorticoid-responsive gene and a key apoptosis regulator that, when over-expressed, can contribute to tumor development, progression and therapeutic resistance. Moreover, synthetic glucocorticoids, like dexamethasone, are frequently used in the treatment of hematopoietic diseases due to its pro-apoptotic properties. We report here that the trithorax protein ASH2L, considered one of the core subunits of H3K4-specific MLL/SET methyltransferase complexes, contributes to anti-apoptotic BCL-XL over-expression and cell survival in patient-derived myeloid leukemia cells. We find that the unliganded glucocorticoid receptor (uGR) and ASH2L interact in a common protein complex through a chromatin looping determined by uGR and ASH2L binding to BCL2L1 specific +58 HRE and promoter region, respectively. Upon addition of dexamethasone, GR and ASH2L recruitment is reduced, BCL-XL expression diminishes and apoptosis is induced consequently. Overall, our findings indicate that uGR and ASH2L may act as key regulatory players of BCL- XL upregulation in AML cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/metabolismo , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Proteína bcl-X/genética , Apoptose , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Regiões Promotoras Genéticas , Elementos de Resposta , Células U937 , Proteína bcl-X/metabolismo
4.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 127-131, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880530

RESUMO

To investigate the relationship between the Erk1/2 signal pathway and neuronal apoptosis in ischemic stroke rats. Male SD(Sprague Dawley)  rats (n = 24) were randomly divided into three groups, each containing 8 rats: sham-operated group, MCAO(Midle cerebral artery oclusion)  group, and MCAO + U0126 intervention group (U0126 group). In in vitro trial, primary cortical nerve cells were divided into three groups: control group, OGD(Oxygen and glucose deprivation)  group, and U0126 intervention group (U0126 group). In vivo protein expression levels of Erk1/2, p-Erk1/2 and Bcl-2 were determined using western blot. The expressions of Bcl-2, Bcl-xl and Bax were assayed using immunohistochemical staining. Nerve cell mortality in cerebral tissue was detected using TUNEL staining. In in vitro trials, cell apoptosis was assayed with flow cytometry and LDH release. The activity of caspase-3 was determined. Nerve cell apoptosis was determined using Hoechst33258 staining method. In in vivo trial, it was found that the protein expression level of p-ERK1/2 in cerebral tissue in the MCAO group was significantly increased, when compared with that of the sham-operated group, while the protein expression level of p-Erk1/2 in the U0126 group was significantly lower than that in the MCAO group. The expression levels of Bcl-2 and Bcl-xl in the MCAO group were significantly lower than the corresponding expression levels in the sham-operated group, while the expressions of Bcl-2 and Bcl-xl in the U0126 group were significantly lower than those in MCAO group. In MCAO group, the expression of Bax was significantly higher than that in the sham-operated group, while Bax expression was higher in U0126 than in MCAO group. There were significantly higher number of dead nerve cells in MCAO group than in the sham-operated group, while nerve cell mortality in U0126 group was significantly lower than in MCAO group. In in vitro trials, flow cytometry revealed significantly higher apoptosis of OGD-treated nerve cells, relative to the control group. Nerve cells exposed to U0126 and treated with ODR (Oxygen-dependent repressor)  were significantly decreased in population, when compared with single OGD treatment group. The LDH release level of nerve cells treated OGD was significantly increased, when compared with that of the control group. However, LDH release level of nerve cells treated with OGD after U0126 intervention was significantly decreased, relative to the single OGD treatment group. The dilution of nerve cell nucleus after OGD treatment was significantly increased, when compared with that of the control group. For nerve cells treated with ODR after U0126 intervention, the nuclear dilution was significantly decreased, relative to that of nerve cell nucleus in the single OGD treatment group. The OGD treatment led to significant increase in nerve cell caspase-3 activity, relative the control group. However, the caspase-3 activity of nerve cells treated with ODR after U0126 intervention was significantly decreased, when compared with single OGD treatment group. The activation of Erk1/2 signal pathway during ischemic stroke promotes apoptosis of nerve cells. Based on these findings, it can be reasonably inferred that the ERK1/2 signal pathway may be an important target for treating ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Isquemia Encefálica/patologia , Butadienos/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Marcação In Situ das Extremidades Cortadas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Nitrilos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
5.
Chem Commun (Camb) ; 55(98): 14765-14768, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31754664

RESUMO

BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.


Assuntos
Isoquinolinas/química , Talidomida/análogos & derivados , Proteína bcl-X/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Linhagem Celular Tumoral , Humanos , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Ligação Proteica , Talidomida/química , Talidomida/metabolismo , Talidomida/farmacologia , Proteína bcl-X/antagonistas & inibidores
6.
Fitoterapia ; 139: 104421, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31730794

RESUMO

Three new prenyloxy chromanone derivatives, aucherine A-C (6, 7 and 9) as well as six known prenylated phloroglucinols (1-5 and 8) were isolated from the aerial parts of Hypericum aucheri Jaub. Et Spach. The structures of the isolated compounds were established by means of spectral techniques (HRESIMS, 1D and 2D NMR). The new compounds were tested on а panel of human tumor cell line using MTT assay. All tested compounds exerted moderate cytotoxicity with IC50 values ranging from 19.6 to 57.8 µM. The influence of the new compounds on some key signaling molecules (procaspase-9 and Bcl-xL), implicated in the regulation of programmed cell death was assessed by Western blot analysis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cromonas/farmacologia , Hypericum/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose , Bulgária , Caspase 9/metabolismo , Linhagem Celular Tumoral , Cromonas/isolamento & purificação , Humanos , Estrutura Molecular , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Prenilação , Proteína bcl-X/metabolismo
7.
Curr Med Sci ; 39(5): 759-765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612394

RESUMO

Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma (HCC), however, reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking. This study was to identify gene-level copy number aberrations (CNAs) related to extrahepatic metastasis-free survival of HCC patients, and further examine the associations between CNAs and gene expression. Array comparative genomic hybridization (aCGH) and expression array were used to analyze gene CNAs and expression levels, respectively. The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months. The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC. We observed that gains at MDM4 and BCL2L1, and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients. Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain, while APC and FBXW7 were significantly downregulated in HCCs with gene loss. We concluded that gene gains at MDM4 and BCL2L1, and losses at APC and FBXW7, with concordant expression changes, were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Proteína 7 com Repetições F-Box-WD/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas/genética , Proteína bcl-X/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Ciclo Celular/metabolismo , Hibridização Genômica Comparativa , Proteína 7 com Repetições F-Box-WD/metabolismo , Feminino , Seguimentos , Dosagem de Genes , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Proteína bcl-X/metabolismo
8.
Artif Cells Nanomed Biotechnol ; 47(1): 3904-3912, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31566021

RESUMO

This study aimed to investigate the effect of Junduqing extractive on proliferation, apoptosis, migration and invasion of nasopharyngeal carcinoma (NPC) cells and the involved mechanism. Junduqing extractive was prepared. CCK-8 assay found that IC50 of Junduqing extractive in HNE-1 cells was 2.99 mg/ml, so its concentration of 1.0, 2.0 and 3.0 mg/ml was selected to perform the following experiments. HNE-1, HNE-2 and HONE1 cells were then divided into four groups: (1) Control (no treatment); (2) 1.0 mg/ml (1.0 mg/ml Junduqing); (3) 2.0 mg/ml (2.0 mg/ml Junduqing) and (4) 3.0 mg/ml (3.0 mg/ml Junduqing). Cell viability, apoptosis, migration and invasion were examined by CCK-8 assay, annexin V-FITC/PI staining, scratch wound assay and transwell assay, respectively. Compared with the control group, the viability, migration rates and invasive capacity of HNE-1, HNE-2 and HONE1 cells with Junduqing treatments decreased significantly. Higher concentration of Junduqing extractive caused lower viability, smaller migration rates and weaker invasive capacity. Compared with the control group, the apoptosis of HNE-1, HNE-2 and HONE1 cells after treatment with 2.0 and 3.0 mg/ml of Junduqing extractive increased remarkably. Levels of Bcl-xL, Mcl-1, Caspase-3, Caspase-8 and Caspase-9 were examined by western blotting. Compared with the control group, the expression of Bcl-xL and Mcl-1 and the expression of Caspase-3, Caspase-8 and Caspase-9 in HNE-1, HNE-2 and HONE1 cells were significantly down-regulated and up-regulated, respectively, after treatment with Junduqing extractive. In conclusion, Junduqing extractive could inhibit the proliferation, migration and invasion, and promote the apoptosis of human NPC cells through down-regulating Mcl-1 and Bcl-xL and up-regulating Caspase-3, Caspase-8 and Caspase-9.


Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Carcinoma Nasofaríngeo/patologia , Proteína bcl-X/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Regulação para Cima/efeitos dos fármacos
9.
Mater Sci Eng C Mater Biol Appl ; 105: 110079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546406

RESUMO

In the present paper, we synthesized and characterized four N-donor polypyridyl copper(II) complexes (C1-C4); [Cu(mono-CN-PIP)2]2+ (C1), [Cu(tri-OMe-PIP)2]2+ (C2), [Cu(di-CF3-PIP)2]2+ (C3) and [Cu(DPPZ)2]2+ (C4). The (Calf-Thymus) CT-DNA binding studies depicted that the complexes could interact with DNA via intercalative mode. All the complexes, particularly C3 and C4 attenuated the proliferation as well as migration of various cancer cells, indicating their anti-cancer and anti-metastatic activity. Additionally, chick embryo angiogenesis (CEA) assay exhibited the inhibition of vascular sprouting in presence of C3 and C4, suggesting their potential in inhibiting the blood vessel growth. Mechanistic studies revealed that the complexes induced the excessive production of cellular reactive oxygen species (ROS) leading to apoptosis through up regulation of p53 and downregulation of Bcl-xL, which might be the plausible mechanisms underlying their anti-cancer properties. To understand the feasibility of practical application of anti-cancer copper complexes C3 and C4, in vivo sub-chronic toxicity study (4 weeks) was performed in C57BL6 mice and the results exhibited almost non-toxic effects induced by these complexes in terms of haematology and serum biochemical analyses, suggesting their biocompatible nature. The current study provides the basis for future advancement of other novel biocompatible metal complexes that could be employed for the therapy of different cancers.


Assuntos
Complexos de Coordenação , Cobre , Substâncias Intercalantes , Melanoma Experimental , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Embrião de Galinha , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Proteína bcl-X/metabolismo
10.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470638

RESUMO

Despite significant advances in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Chemoradiation therapy is a rational approach that has already proven beneficial for several malignancies. However, the existence of toxicity to normal tissue is a serious limitation of this treatment modality. The aim of the present study is to investigate the ability of polar steroids from starfish Patiria (=Asterina) pectinifera to enhance the efficacy of radiation therapy in colorectal carcinoma cells. The cytotoxic activity of polar steroids and X-ray radiation against DLD-1, HCT 116, and HT-29 cells was determined by an MTS assay. The effect of compounds, X-ray, and their combination on colony formation was studied using the soft agar method. The molecular mechanism of the radiosensitizing activity of asterosaponin P1 was elucidated by western blotting and the DNA comet assay. Polar steroids inhibited colony formation in the tested cells, and to a greater extent in HT-29 cells. Asterosaponin P1 enhanced the efficacy of radiation and, as a result, reduced the number and size of the colonies of colorectal cancer cells. The radiosensitizing activity of asterosaponin P1 was realized by apoptosis induction through the regulation of anti- and pro-apoptotic protein expression followed by caspase activation and DNA degradation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/genética , Asterina/química , Regulação Neoplásica da Expressão Gênica , Compostos Policíclicos/farmacologia , Radiossensibilizantes/farmacologia , Saponinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Células HCT116 , Células HT29 , Humanos , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação , Radiossensibilizantes/química , Radiossensibilizantes/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Ensaio Tumoral de Célula-Tronco , Raios X , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
11.
Life Sci ; 235: 116844, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499069

RESUMO

AIMS: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. MAIN METHODS: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/ß-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3ß, which in turn upregulated Wnt1, ß-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KEY FINDINGS: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3ß/Caspase-3 activity and enhancing the expression of Wnt1/ß-catenin/Neuro D1/Cyclin D1 and Bcl-xL. SIGNIFICANCE: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Neurogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
12.
Nat Commun ; 10(1): 3667, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413255

RESUMO

Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Regulação Alostérica , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos da radiação , Fluoruracila/farmacologia , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos , Radiação , Regeneração/efeitos da radiação , Proteína bcl-X/efeitos dos fármacos , Proteína bcl-X/metabolismo , Proteínas rac1 de Ligação ao GTP/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo
13.
Chem Biol Interact ; 311: 108786, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401087

RESUMO

Naturally occurring oleanolic acid (OA) possesses a hepatoprotective activity and ability to inhibit proliferation of human hepatocellular carcinoma cells. Both properties might be related to its anti-inflammatory activity. Its low bioavailability justifies the search for more hydrophilic OA derivatives. The aim of this study was the design and synthesis of four novel OA oxime derivatives conjugated with succinic acid at the C-3 position of oleanane skeleton structure and evaluation of their effect on NF-κB and STATs expression and activation in HepG2 cells. The expression of NF-κB and cyclooxygenase-2 (COX-2), STAT5A/B and STAT3 with its target genes: BAX, BCL-XL and MYC was evaluated after 24 h treatment with tested compounds. The comparison of the levels of cytosolic and nuclear NF-κB subunits p50, p65 and STATs proteins was used as the measure of their activation. The results pointed out the 3-succinyloxyiminoolean-12-en-28-oic acid morpholide (SMAM) as the most potent modulator of NF-κB and STAT3. SMAM significantly reduced the expression and activation of NF-κB as well as its nuclear protein level of p65 subunit. This compound also reduced the expression and activation of STAT3 and STAT5A/B. Combined effect of SMAM on these transcription factors resulted in reduced expression of COX-2, MYC and anti-apoptotic BCL-XL genes. Simultaneously, the increased expression of pro-apoptotic BAX gene was observed. In the cells treated with 3-succinyloxyiminoolean-12-en-28-oic acid (SMAA) the increased expression of BAX was also found. The effects of 3-succinyloxyiminoolean-12-en-28-oic acid benzyl ester (SMAEB) and 3-succinyloxyiminoolean-12-en-28-oic acid methyl ester (SMAEM) were moderate and ambiguous in relation to the tested factors. Moreover, the coordinated action of SMAM on NF-κB and STAT3 confirms their close association in HepG2 cells. We conclude that SMAM efficiently downregulates the key elements of signaling pathways involved in inflammatory driven HCC. Thus, may be considered as a potential chemopreventive or therapeutic agent in this type of cancer.


Assuntos
NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Oximas/farmacologia , Fatores de Transcrição STAT/metabolismo , Ácido Succínico/química , Carcinoma Hepatocelular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , NF-kappa B/genética , Oximas/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/genética , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
14.
Mol Cell Biochem ; 461(1-2): 151-158, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31352611

RESUMO

Fluorouracil (5-FU) which has been widely used in postoperative adjuvant therapy in patients with colon cancer, remains the main backbone of combination treatment of patients with colon cancer. However, the efficacy of 5-FU alone in colorectal cancer patients with BRAFV600E is not clear. In this study, we demonstrated that BRAFV600E confers sensitivity to 5-FU in vitro and in vivo xenograft model, using the paired isogenic colorectal cancer cell lines RKO with either BRAF Wild Type (WT)(+/-) or mutant (Mut) (600E/-). Our results revealed 5-FU preferably induces marked apoptosis in BRAF-mutant colorectal cancer cells, through attenuating expression of Bcl-xL and activation caspase-3/9 pathway, eventually conferring the anti-tumor efficacy of 5-FU in vitro and in vivo. Meanwhile, expression of Bcl-xL remained unchanged in BRAF WT group after treatment of 5-FU, although low extent of anti-tumor activity of 5-FU still being observed. In conclusion, these results provided a better understanding of clinical outcome of 5-FU between BRAF WT and mutant colorectal cancer patients, and suggested the inhibition of Bcl-xL might present an alternative strategy to enhance the therapeutic efficacy of 5-FU in colorectal cancer patients with BRAF mutation.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/genética , Regulação para Baixo/efeitos dos fármacos , Fluoruracila/farmacologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteína bcl-X/genética , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Proteína bcl-X/metabolismo
15.
PLoS One ; 14(7): e0219782, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31329620

RESUMO

Apoptotic protease-activating factor 1 (Apaf-1) is a component of apoptosome, which regulates caspase-9 activity. In addition to apoptosis, Apaf-1 plays critical roles in the intra-S-phase checkpoint; therefore, impaired expression of Apaf-1 has been demonstrated in chemotherapy-resistant malignant melanoma and nuclear translocation of Apaf-1 has represented a favorable prognosis of patients with non-small cell lung cancer. In contrast, increased levels of Apaf-1 protein are observed in the brain in Huntington's disease. The regulation of Apaf-1 protein is not yet fully understood. In this study, we show that etoposide triggers the interaction of Apaf-1 with Cullin-4B, resulting in enhanced Apaf-1 ubiquitination. Ubiquitinated Apaf-1, which was degraded in healthy cells, binds p62 and forms aggregates in the cytosol. This complex of ubiquitinated Apaf-1 and p62 induces caspase-9 activation following MG132 treatment of HEK293T cells that stably express bcl-xl. These results show that ubiquitinated Apaf-1 may activate caspase-9 under conditions of proteasome impairment.


Assuntos
Fator Apoptótico 1 Ativador de Proteases/metabolismo , Caspase 9/metabolismo , Proteínas Culina/metabolismo , Ubiquitinação , Ativação Enzimática/efeitos dos fármacos , Etoposídeo/farmacologia , Células HEK293 , Humanos , Leupeptinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos , Proteína bcl-X/metabolismo
16.
J Microbiol Biotechnol ; 29(8): 1193-1203, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31280521

RESUMO

We investigated the protective effects of 3-bromo-4,5-dihydroxybenzaldehyde (BDB) from Polysiphonia morrowii Harvey against hydrogen peroxide (H2O2)-induced apoptosis in Vero cells. BDB exhibited scavenging activity for DPPH, hydroxyl, and alkyl radicals. BDB also inhibited H2O2-induced lipid peroxidation, cell death, and apoptosis in Vero cells by inhibiting the production of ROS. To evaluate the molecular mechanisms of apoptosis inhibition, the expression of Bax/Bcl-xL and NF-κB was assessed by western blot assay. BDB significantly suppressed the cleavage of caspase-9 and PARP and reduced Bax levels in H2O2-induced Vero cells. Besides, BDB suppressed the phosphorylation of NF-κB and the translocation of p65 in H2O2-induced cells. Furthermore, we evaluated the effect of BDB on ROS production, cell death, and lipid peroxidation in an H2O2-stimulated zebrafish embryo model. Taken together, these results indicated that ROS generation and cell death were significantly inhibited by BDB in zebrafish embryos, thereby proving that BDB exerts excellent antioxidant activity in vitro and in vivo.


Assuntos
Benzaldeídos/farmacologia , Peróxido de Hidrogênio/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rodófitas/química , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular , Feminino , Peroxidação de Lipídeos , Masculino , Modelos Animais , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Vero , Peixe-Zebra/anormalidades , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
17.
Int J Mol Sci ; 20(13)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262032

RESUMO

Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10-45 µM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs.


Assuntos
Antipsicóticos/farmacologia , Carcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Trifluoperazina/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteína bcl-X/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antipsicóticos/uso terapêutico , Apoptose , Carcinoma/metabolismo , Linhagem Celular , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação para Baixo , Humanos , Camundongos , Trifluoperazina/uso terapêutico , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/patologia , Proteína bcl-X/genética
18.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323961

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Glioblastoma/metabolismo , Fases de Leitura Aberta/genética , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Interleucina-6/metabolismo , Fator de Transcrição STAT3/genética , Proteína bcl-X/metabolismo
19.
Mol Med Rep ; 20(2): 879-886, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173228

RESUMO

Lipid storage droplet protein 5 (LSDP5) is specifically expressed in tissues with high oxidative metabolism such as liver and heart. The present study aimed to explored the role of LSDP5 in sodium palmitate­induced lipotoxicity in LO2 normal human liver cells. LO2 cells were treated with various concentrations of sodium palmitate (25, 50, 75, 100, 125 and 150 µmol/l) for 12, 24 and 48 h, and cell viability was determined by Cell Counting Kit­8. Subsequently, LO2 cells were exposed to 100 µmol/l sodium palmitate for 48 h to induce lipotoxicity (Model). Lipotoxicity Model LO2 cells were also transfected with pCMV5­LSDP5 overexpression vector, and reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and apoptotic rates were measured. The contents of non­esterified fatty acid (NEFA), malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured. The expression levels of LSDP5, and apoptosis­, mitochondrial­, lipid metabolism­related factors were detected using reverse transcription­quantitative polymerase chain reaction and western blot assays. The results indicated that sodium palmitate exposure inhibited cell viability and induced lipotoxicity in LO2 cells. LSDP5 overexpression decreased ROS and apoptotic rates, and reduced NEFA and MDA content. LSDP5 transfection rescued the loss of MMP and elevated SOD content in lipotoxicity Model LO2 cells. In addition, LSDP5 upregulated the expression levels of B­cell lymphoma­2, acetyl­CoA carboxylase1/2 and fatty acid synthase (Fas), whereas the expression levels of activated­caspase­3, Bcl­2­associated X protein, cytochrome c, cytochrome c oxidase subunits IV, carnitine palmitoyltransferase 1a and peroxisome proliferator­activated receptors α levels were downregulated. LSDP5 may produce a protective effect on sodium palmitate­induced lipotoxicity in LO2 cells by regulating lipid metabolism­related factors.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Palmítico/farmacologia , Perilipina-5/genética , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Relação Dose-Resposta a Droga , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo , PPAR alfa/genética , PPAR alfa/metabolismo , Perilipina-5/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
20.
J Recept Signal Transduct Res ; 39(1): 87-97, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31215288

RESUMO

Deregulation of the normal cellular apoptotic function is a fundamental element in the etiology of most cancers and the anti-apoptotic B cell lymphoma 2 (BCL­2) protein family is known to play crucial role in the regulation of this function. Overexpression of this protein family has been implicated in some cancers, such that agents that could inhibit their over-activity are now being explored for anticancer drug development. A number of studies have revealed the anticancer potential of Morinda lucida-derived extracts and compounds. In search of more inhibitors of this anti-apoptotic protein family from plant resources, 47 compounds, identified in Morinda lucida Benth (Rubiaceae) were screened for their inhibitory activities against BCL-XL, BCL-2, and MCL-1 by molecular docking using BINDSURF, while binding interactions of the top compounds were viewed with PyMOL. Druglikeness and Absorption-Distribution-Metabolism-Excretion (ADME) parameters of the top 6 compounds from docking study were evaluated using SuperPred webserver. Results revealed that out of the 47 compounds, 2 triterpenes (ursolic acid and oleanolic acid) and 4 phytosterols (cycloartenol, campesterol, stigmasterol, and ß-sitosterol) have higher binding affinities for the selected BCL-2 proteins, compared to known standard inhibitors; these compounds also fulfill oral drugability of Lipinski rule of five. Therefore, since these Morinda lucida-derived phytosterols and triterpenes show high binding affinity toward the selected anti-apoptotic proteins and exhibited good drugability characteristics, they qualify for further study on drug development against cancers characterized by overexpression of this family of protein.


Assuntos
Morinda/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Fitosteróis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Triterpenos/farmacologia , Proteína bcl-X/antagonistas & inibidores , Simulação por Computador , Humanos , Ligantes , Modelos Moleculares , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fitosteróis/química , Ligação Proteica , Conformação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Triterpenos/química , Proteína bcl-X/metabolismo
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