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1.
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
2.
Nat Commun ; 10(1): 2532, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182717

RESUMO

Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/metabolismo , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Knockout , Camundongos Nus , Mutação , Transplante de Neoplasias , Multimerização Proteica , Quinases raf/antagonistas & inibidores , Quinases raf/genética , Proteínas ras/metabolismo
3.
Artif Cells Nanomed Biotechnol ; 47(1): 1524-1532, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30982359

RESUMO

Proteinuria is one of the most important clinical features of nephrotic syndrome (NS). Injury of podocyte has been proved to contribute to the occurrence of proteinuria. This study explored the effects of geniposide (GEN) on lipopolysaccharide (LPS)-caused murine kidney podocyte MPC5 apoptosis and autophagy. Viability and apoptosis of MPC5 cells were respectively detected with the help of CCK-8 assay and Guava Nexin assay. 3-Methyladenine (3-MA) was used as an autophagy inhibitor, while rapamycin as autophagy activator. Si-Beclin-1 was transfected in MPC5 cells to down-regulate the expression of Beclin-1. We found that LPS stimulation significantly caused MPC5 cell viability reduction, apoptosis and autophagy (P < .05 or P < .01). GEN treatment remarkably alleviated the LPS-caused MPC5 cell viability reduction and apoptosis, but promoted cell autophagy (P < .05). Moreover, 3-MA incubation or si-Beclin-1 transfection notably weakened the effects of GEN on LPS-caused MPC5 cell apoptosis and autophagy (P < .05), while rapamycin had opposite effects (P < .05). Furthermore, GEN activated Ras/Raf/MEK/ERK pathway in LPS-treated MPC5 cells (P < .05). In conclusion, this research verified the protective effects of GEN on podocytes damage. GEN alleviates LPS-caused apoptosis of murine kidney podocytes by activating Ras/Raf/MEK/ERK-mediated cell autophagy. Highlights: LPS causes podocyte MPC5 apoptosis and autophagy. GEN alleviates LPS-caused MPC5 cell apoptosis, but promotes cell autophagy. 3-MA or si-Beclin-1 weakens the effects of GEN on LPS-treated MPC5 cells. Rapamycin strengthens the effects of GEN on LPS-treated MPC5 cells. GEN activates Ras/Raf/MEK/ERK pathway in LPS-treated MPC5 cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Iridoides/farmacologia , Rim/citologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Inativação Gênica , Camundongos , Podócitos/citologia , Podócitos/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo
4.
Life Sci ; 223: 128-136, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876941

RESUMO

AIMS: Liquorice is a widely used herbal medicine for treating various diseases native to southern Europe and parts of Asia. Isoliquiritin (ISL), a licorice root-derived flavonoid, has been reported to exhibit antioxidant, anti-inflammatory, anti-genotoxic activity and anti-depression activities. This study was aimed to explore the pro-angiogenic activity of ISL and explicate the underlying mechanism. MAIN METHODS: In vitro, ISL-treated human umbilical vein endothelial cells (HUVECs) were analyzed for cell viability, cell migration and tube formation. In vivo, pro-angiogenic effects were evaluated for the intersegmental vessels (ISVs) formation in transgenic zebrafish embryos [Tg(fli-1: EGFP)]. Furthermore, a blocking assay with eight pathways-specific kinase inhibitors were also used to determine the potential pro-angiogenic mechanism of ISL. KEY FINDINGS: ISL counteracted tyrosine kinase inhibitor II (VRI)-induced endothelial cell apoptosis and promoted cell migration and tube formation in HUVECs. ISL markedly rescued ISVs loss induced by VRI in zebrafish embryos, probably by activating vascular endothelial growth factor receptor-2 (VEGFR-2), phosphoinositide 3-kinase (PI3K), Raf and mitogen-activated protein kinase (MEK)-dependent signaling pathways. SIGNIFICANCE: Our study first discovered and confirmed the pro-angiogenic activity of ISL both in HUVECs and zebrafish. Thus, ISL could be developed as a potential therapeutic agent by the role of pro-angiogenic activity for the treatment of cardiovascular diseases, cerebrovascular diseases and other vascular diseases.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Chalcona/análogos & derivados , Desenvolvimento Embrionário/efeitos dos fármacos , Glucosídeos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Peixe-Zebra/embriologia , Quinases raf/metabolismo , Animais , Animais Geneticamente Modificados , Vasos Sanguíneos/embriologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Chalcona/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/enzimologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Peixe-Zebra/genética
5.
J Photochem Photobiol B ; 194: 46-55, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30925276

RESUMO

Human papillomavirus (HPV) infection is linked to several diseases, the most prominent of which are cervical cancer and genital condyloma acuminatum. Previous studies have suggested an effective role for 5-aminolevulinic acid photodynamic therapy (ALA-PDT) against various cancers by the induction of autophagy and apoptosis. However, few reports have focused on the effectiveness of ALA-PDT on HPV related disorders. To identify the role of ALA-PDT in the context of HPV infection, we initially investigated 111 patients suffering from genital condyloma acuminatum. HPV viral load detected before and after ALA-PDT treatment was compared during this procedure; a significant difference was noted. HeLa (HPV18) cells were exposed to ALA-PDT in vitro to further explore the underlying mechanisms. Western blot analysis showed that ALA-PDT induces LC3II and p62 expression, along with the up regulation of caspase-3 and cleaved caspase-3. Our study also demonstrated that ALA-PDT treatment inhibits the proliferation of HeLa cells in a dose dependent manner and effectively reduces HPV viral load via autophagy and apoptosis by regulating the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways. Hydroxychloroquine (HCQ), although it inhibited autophagy degradation, functioned to activate reactive oxygen species (ROS) levels of ALA-PDT to enhance the observed effect. These findings suggest strategies for the improvement of PDT efficacy in patients.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Ácidos Levulínicos/farmacologia , Papillomaviridae/fisiologia , Fotoquimioterapia , Carga Viral/efeitos dos fármacos , Carga Viral/efeitos da radiação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Autofagia/efeitos dos fármacos , Autofagia/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Papillomaviridae/efeitos dos fármacos , Papillomaviridae/efeitos da radiação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo
6.
Phytomedicine ; 59: 152895, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30913453

RESUMO

BACKGROUND: There have been some reports implicating the pharmacologic action of Dihydrosanguinarine (DHSA), but little research including the effects of it on cancer cells. PANC-1 cells have mutations in K-Ras and TP53, which respectively express mutant K-Ras and p53 protein, and the mutations in Ras/p53 have been believed with closely relationship to the occurrence of various tumors. PURPOSE: To reveal the inhibition of Dihydrosanguinarine on pancreatic cancer cells (PANC-1 and SW1990) proliferation by inducing G0/G1 and G2/M phase arrest via the downregulation of mut-p53 protein, inducing apoptosis and inhibiting invasiveness through the Ras/Mek/Erk signaling pathway. METHODS: Human pancreatic cancer cell lines were cultured with cisplatin and DHSA. Then, cell proliferation, the cell cycle and apoptosis were measured by CCK-8 and flow cytometry. The migratory and invasive abilities of pancreatic cancer cells were evaluated by transwell assay. The expression levels of mRNA and protein were measured by RT-PCR and western blotting. RESULTS: The results showed that DHSA treatment inhibited cell proliferation, migration and invasion in a time- and dose-dependent manner and led to induction of cell cycle arrest and apoptosis. G0/G1 and G2/M phase arrest inhibited the viability of PANC-1 cells by downregulating the expression of mut-p53 protein. Decreased levels of C-Raf and Erk phosphorylation in DHSA-treated PANC-1 and SW1990 cells were observed in a time- and dose-dependent manner. However, the total expression of p53 and Ras proteins had a different change in PANC-1 and SW1990 cells. CONCLUSIONS: Our findings offer the novel perspective that DHSA inhibits pancreatic cancer cells through a bidirectional regulation between mut-p53/-Ras and WT-p53/-Ras to restore the dynamic balance by Ras and p53 proteins.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzofenantridinas/farmacologia , Isoquinolinas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
7.
Mol Med Rep ; 19(4): 3105-3113, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816458

RESUMO

Autophagy regulates the metabolism, survival and function of numerous types of cell, including cells that comprise the cardiovascular system. The dysfunction of autophagy has been demonstrated in atherosclerosis, restenotic lesions and hypertensive vessels. As a member of the Ras GTPase superfamily, Rab7 serves a significant role in the regulation of autophagy. The present study evaluated how Rab7 affects the proliferation and invasion, and phenotypic transformations of aortic dissection (AD) smooth muscle cells (SMCs) via autophagy. Rab7 was overexpressed in AD tissues and the percentage of synthetic human aortic SMCs (HASMCs) was higher in AD tissues compared with NAD tissues. Downregulation of Rab7 decreased cell growth, reduced the number of invasive cells and decreased the percentage cells in the G1 phase. Autophagy of HASMCs was inhibited following Rab7 knockdown. Inhibition of autophagy with 3­methyladenine or Rab7 knockdown suppressed the phenotypic conversion of contractile to synthetic HASMCs. The action of Rab7 may be mediated by inhibiting the Ras/Raf/mitogen­activated protein kinase (MAPK) kinase (MEK)/extracellular signal related kinase (ERK) signaling pathway. In conclusion, the results revealed that Rab7­mediated autophagy regulated the behavior of SMCs and the phenotypic transformations in AD via activation of the Ras/Raf/MEK/ERK signaling pathway. The findings of the present study may improve understanding of the role Rab7 in the molecular etiology of AD and suggests the application of Rab7 as a novel therapeutic target in the treatment of human AD.


Assuntos
Aneurisma Dissecante/etiologia , Aneurisma Dissecante/metabolismo , Autofagia , Miócitos de Músculo Liso/metabolismo , Fenótipo , Transdução de Sinais , Proteínas rab de Ligação ao GTP/metabolismo , Ciclo Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo
9.
Radiat Res ; 191(3): 237-244, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30694732

RESUMO

Development of oral mucositis represents a rate-limiting factor in radiation therapy for the treatment of head and neck, as well as other cancers. In this work, we investigated the treatment effect of ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) on radiation-induced oral mucositis, and examined possible underlying mechanisms. Male Sprague-Dawley rats were exposed to 20 Gy X-ray irradiation (single dose, cranial localization) to induce oral mucositis. Possible therapeutic effects of ecdysterone on radiation-induced oral mucositis were investigated by monitoring weights, direct observations, visual scoring method and evaluation of hematoxylin and eosin staining. Assessments of leukocyte common antigen and proliferating cell nuclear antigen staining were also performed in the damaged areas of tongues harvested after irradiation, and changes in signaling pathways were investigated using Western blotting. The development and progression of radiation-induced oral mucositis in this model was similar to that observed in clinic patients. Ecdysterone effectively improved radiation-induced oral mucositis as assessed by direct observation and histopathology, and also increased proliferation of matrix cells, since the Ras-Raf-ERK signal pathway was found to be activated by its use. It was concluded that orally administered ecdysterone accelerated the healing process in a rat model of radiation-induced oral mucositis by upregulating the Ras-Raf-ERK signal pathway.


Assuntos
Ecdisterona/farmacologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Estomatite/patologia , Estomatite/fisiopatologia , Animais , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Doses de Radiação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Quinases raf/metabolismo , Proteínas ras/metabolismo
10.
Int J Mol Sci ; 20(3)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678221

RESUMO

Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tumor adaptation to microenvironmental hypoxia, and it also exerts important roles in angiogenesis and tumor development. Vanillic acid is a dietary phenolic compound reported to exhibit anticancer properties. However, the mechanisms by which vanillic acid inhibits tumor growth are not fully understood. Here, we investigated the effect of vanillic acid on HIF-1α activation. Vanillic acid significantly inhibits HIF-1α expression induced by hypoxia in various human cancer cell lines. Further analysis revealed that vanillic acid inhibited HIF-1α protein synthesis. Neither the HIF-1α protein degradation rate nor the steady-state HIF-1α mRNA levels were affected by vanillic acid. Moreover, vanillic acid inhibited HIF-1α expression by suppressing mammalian target of rapamycin/p70 ribosomal protein S6 kinase/eukaryotic initiation factor 4E-binding protein-1 and Raf/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways. We found that vanillic acid dose-dependently inhibited VEGF and EPO protein expressions and disrupted tube formation. The results suggest that vanillic acid effectively inhibits angiogenesis. Flow cytometry analysis demonstrated that vanillic acid significantly induced G1 phase arrest and inhibited the proliferation of human colon cancer HCT116 cells. In vivo experiments confirmed that vanillic acid treatment caused significant inhibition of tumor growth in a xenografted tumor model. These studies reveal that vanillic acid is an effective inhibitor of HIF-1α and provides new perspectives into the mechanism of its antitumor activity.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ácido Vanílico/uso terapêutico , Quinases raf/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico
11.
Nat Commun ; 10(1): 224, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30644389

RESUMO

Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors. In contrast, SHP2 dephosphorylates KRAS, a process that is required to maintain dynamic canonical KRAS GTPase cycle. Notably, Src- and SHP2-mediated regulation of KRAS activity extends to oncogenic KRAS and the inhibition of SHP2 disrupts the phosphorylation cycle, shifting the equilibrium of the GTPase cycle towards the stalled 'dark state'.


Assuntos
Antineoplásicos/uso terapêutico , GTP Fosfo-Hidrolases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Células HEK293 , Humanos , Masculino , Camundongos SCID , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/metabolismo
12.
Biomed Pharmacother ; 109: 1640-1649, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551418

RESUMO

Acute lymphoblastic leukemia (ALL) is characterized by abnormal lymphoblasts accumulation in the bone marrow and blood. Despite great efforts have been made in exploring novel therapeutic method, the prognosis of children with ALL is still unsatisfied. Glucocorticoid (GC) resistance is a great obstacle for the clinical treatment of ALL. Therefore, it is essential to investigate the molecular mechanism underlying the GC resistance. According to previous reports, long noncoding RNAs (lncRNAs) are involved in drug resistance of various human cancers. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) has been reported in several human malignancies due to its oncogenic property. However, the molecular mechanism of HOXA-AS2 involved in the GC resistance of ALL still needs to be further clarified. At first, we found that lncRNA HOXA-AS2 was highly expressed both in prednisone insensitive ALL cell lines and patient samples. Gain or loss-of-function assays revealed that HOXA-AS2 enhanced GC resistance via promoting cell proliferation and inhibiting cell apoptosis. Furthermore, we validated that HOXA-AS2 upregulated HOXA3, thereby activating EGFR/Ras/Raf/MEK/ERK signaling pathway. Our findings showed that HOXA-AS2 may be a potential therapeutic target for ALL patients with poor GC resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucocorticoides/farmacologia , Proteínas de Homeodomínio/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Longo não Codificante/biossíntese , Proteína 2 Semelhante ao Fator 7 de Transcrição/farmacologia , Adolescente , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/metabolismo , Feminino , Glucocorticoides/uso terapêutico , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisona/farmacologia , Prednisona/uso terapêutico , Quinases raf/metabolismo , Proteínas ras/metabolismo
13.
Eur J Med Chem ; 158: 144-166, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30216849

RESUMO

Frequent oncogenic mutations have been identified in MAPK (mitogen-activated protein kinase) signaling pathway components. As a result, MAPK pathway is associated with human cancer initiation, in particular RAF (rapidly accelerated fibrosarcoma) component. The mutation in RAF component leads to auto-activation of MAPK signaling pathway, stimulating the uncontrolled cell growth and proliferation. In last few years, diverse chemical scaffolds have been identified as RAF inhibitors. Most of these scaffolds show potent anti-cancer activity. The present review highlights the recent investigations of RAF inhibitors during the last five years.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Humanos , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases raf/química , Quinases raf/metabolismo
14.
Biomed Pharmacother ; 105: 282-289, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29860220

RESUMO

Liver fibrosis is a typical complication of chronic liver diseases resulting in cirrhosis that remains a major public health problem. The aim of the present study was to identify the role of interleukin-9 (IL-9), an important regulator of inflammation and autoimmune diseases, in hepatic fibrosis progression. It was found that the expression of IL-9 was significantly increased in liver tissues of liver cirrhosis patients compared with that in healthy controls. Moreover, CXCL10, not CXCL9 or CXCL11, induced IL-9 expression in the liver tissue. Overexpression of IL-9 enhanced the severity of liver fibrosis in the carbon tetrachloride (CCl4)-induced liver fibrosis model. Western Blotting analysis revealed that this pro-fibrosis bioactivity of IL-9 was attributed to its selective activation of Raf/MEK/ERK signaling. Finally, administration of neutralizing anti-IL-9 antibody ameliorated liver fibrosis and attenuated the activation of hepatic stellate cells in mice. All these findings indicate that IL-9 plays a deleterious role in the development and progression of liver fibrosis, and IL-9 based immunotherapy may prove to be a promising strategy for the treatment of liver fibrosis.


Assuntos
Quimiocina CXCL10/metabolismo , Interleucina-9/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Sistema de Sinalização das MAP Quinases , Quinases raf/metabolismo , Adulto , Idoso , Animais , Feminino , Humanos , Recém-Nascido , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Testes de Neutralização
15.
Genetics ; 209(2): 523-535, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29615470

RESUMO

The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cß, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of, or in parallel to, the Gq-Rho pathway. Through epistasis experiments, we found that the core ERK MAPK cascade is required for Gq-Rho regulation of locomotion, but that the canonical ERK activator LET-60/Ras may not be required. Through neuron-specific rescue experiments, we found that the ERK pathway functions in head acetylcholine neurons to control Gq-dependent locomotion. Additionally, expression of activated LIN-45/Raf in head acetylcholine neurons is sufficient to cause an exaggerated waveform phenotype and hypersensitivity to the acetylcholinesterase inhibitor aldicarb, similar to an activated Gq mutant. Taken together, our results suggest that the ERK MAPK pathway modulates the output of Gq-Rho signaling to control locomotion behavior in C. elegans.


Assuntos
Caenorhabditis elegans/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Locomoção , Sistema de Sinalização das MAP Quinases , Proteínas rho de Ligação ao GTP/metabolismo , Aldicarb/farmacologia , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Inibidores da Colinesterase/farmacologia , Epistasia Genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
16.
Tohoku J Exp Med ; 244(3): 187-193, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29503347

RESUMO

The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4+ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8+ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Janus Quinases/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Quinases raf/metabolismo
17.
J Cancer Res Ther ; 14(Supplement): S125-S131, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29578162

RESUMO

Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is triggered by BCR/ABL tyrosine kinase which activates the downstream signaling pathways, such as Akt/mTOR, RAF/MEK/ERK, and STAT5 pathways. Curcumin has been shown to have inhibitory effects on cancers by inducing apoptosis and autophagy. We demonstrated that curcumin inhibited activation of Akt-mTOR, ABL/STAT5 pathways, inhibited cell proliferation, and induced apoptosis in Ph + ALL cells. Experiments here, were conducted to determine whether autophagy via MEK/ERK pathway involved in anti-leukemia effect of curcumin in Ph + ALL. Materials and Methods: Ph + ALL cell line SUP-B15 was treated with curcumin. Cytotoxic activity of curcumin was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Signaling protein and specific maker of autophagy and conversion of LC3-I to LC3-II were determined by Western blot analysis. Cell apoptosis was determined by flow cytometry. Results: Curcumin treatment up-regulated the activation of RAF/MEK/ERK at 4 h and 8 h after curcumin exposure in SUP-B15 cells, curcumin treatment induced autophagy at exactly 4 h and 8 h after curcumin exposure. Curcumin exerted cytotoxic activity against SUP-B15 cells at 4 h and 8 h, which was independent of apoptosis. MEK specific inhibitor U0126 inhibited the occurrence of autophagy, and then blocked curcumin-induced cytotoxicity at 4 h and 8 h. Conclusions: Curcumin induce autophagic cell death in SUP-B15 cells via activating RAF/MEK/ERK pathway. These findings suggest that autophagic mechanism contribute to the curcumin-induced early SUP-B15 cell death, and autophagy is another anti-leukemia mechanism of curcumin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Curcumina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/metabolismo
18.
Dokl Biochem Biophys ; 478(1): 14-17, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29536301

RESUMO

The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Terapia de Alvo Molecular , Carcinoma de Células Renais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo
19.
Molecules ; 23(2)2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29438315

RESUMO

BACKGROUND: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. METHODS: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. RESULTS: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. CONCLUSIONS: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Piridonas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzopiranos/síntese química , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Concentração Inibidora 50 , Isoxazóis/síntese química , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/síntese química , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Survivina , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/antagonistas & inibidores , Quinases raf/genética , Quinases raf/metabolismo
20.
Int J Mol Med ; 41(4): 2389-2396, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29393362

RESUMO

The RAS/RAF/MEK/ERK pathway is one of the most frequently dysregulated kinase cascades in human cancer, that facilitate the proliferation and survival of cancers driven by growth factor receptors. Tanshinone IIA (Tan-IIA) was extracted from Danshen (Salviae Miltiorrhizae Radix). Tan-IIA inhibition of the proliferation of gastric cancer are well documented, but the molecular mechanisms of Tan-IIA inhibition of gastric cancer have not been well elucidated. We evaluated the protein expression of vascular epidermal growth factor receptor (VEGFR), human epidermal growth factor receptor 2 (HER2), Ras, Raf, MEK, ERK, PARP, caspase-3 and ß-actin in AGS cells by western blotting. The results showed that AGS cells treated with Tan-IIA upregulated the protein expression of PARP and caspase-3 but decreased VEGFR, HER2, Ras, Raf, MEK and ERK time- and dose-dependently. These findings demonstrated that Tan-IIA inhibited human gastric cancer AGS cells; one of the molecular mechanisms may be through decreasing the protein expression of VEGFR and HER2, then blocking the Ras/Raf/MEK/ERK pathway to induce the activation of PARP and caspase-3 to induce apoptosis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Abietano/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Quinases raf/metabolismo , Proteínas ras/metabolismo
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