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1.
Biomed Pharmacother ; 148: 112748, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35219117

RESUMEN

Paeoniae Radix (PR) has a great therapeutic value in many clinical applications; however, the presence of various bioactive compounds and its complicated effects on human health makes its precise mechanisms of action unclear. This study investigated the effects of PR at the molecular pathway level by profiling genome-wide gene expression changes following dose-dependent treatment of human lung cancer cells (A549) with PR water extract (WPR), PR ethanol extracts (EPR), as well as their individual components. We found that PR exerts anticancer effects in A549 cells by regulating numerous pathways. Specifically, EPR and two compounds, namely, hederagenin (HG) and oleanolic acid (OA), significantly downregulate the Aurora B pathway. Furthermore, we generated an integrated PR extracts-compounds-target genes network in the Aurora B pathway to understand their interactions. Our findings reinforce that inhibiting Aurora kinase activity is a therapeutic target for treating cancers, providing the potential for novel mechanisms of action for PR and its components against lung cancer.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Perfilación de la Expresión Génica/métodos , Neoplasias Pulmonares/patología , Paeonia/química , Extractos Vegetales/farmacología , Células A549 , Aurora Quinasa B/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/metabolismo , Raíces de Plantas/química
2.
Biomed Pharmacother ; 147: 112645, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35051862

RESUMEN

Plants are a rich source for bioactive compounds. However, plant extracts can harbor a mixture of bioactive molecules that promote divergent phenotypes and potentially have confounding effects in bioassays. Even with further purification and identification, target deconvolution can be challenging. Corynoline and acetylcorynoline, are phytochemicals that were previously isolated through a screen for compounds able to induce mitotic arrest and polyploidy in oncogene expressing retinal pigment epithelial (RPE) cells. Here, we shed light on the mechanism by which these phytochemicals can attack human cancer cells. Mitotic arrest was coincident to the induction of centrosome amplification and declustering, causing multi-polar spindle formation. Corynoline was demonstrated to have true centrosome declustering activity in a model where A549 cells were chemically induced to have more than a regular complement of centrosomes. Corynoline could inhibit the centrosome clustering required for pseudo-bipolar spindle formation in these cells. The activity of AURKB, but not AURKA or polo-like kinase 4, was diminished by corynoline. It only partially inhibited AURKB, so it may be a partial antagonist or corynoline may work upstream on an unknown regulator of AURKB activity or localization. Nonetheless, corynoline and acetylcorynoline inhibited the viability of a variety of human cancer derived cell lines. These phytochemicals could serve as prototypes for a next-generation analog with improved potency, selectivity or in vivo bioavailability. Such an analog could be useful as a non-toxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.


Asunto(s)
Aurora Quinasa B/efectos de los fármacos , Alcaloides de Berberina/farmacología , Mitosis/efectos de los fármacos , Fitoquímicos/farmacología , Poliploidía , Células A549 , Apoptosis/efectos de los fármacos , Aurora Quinasa A/efectos de los fármacos , Línea Celular Tumoral , Centrosoma/efectos de los fármacos , Humanos
3.
Toxicol Lett ; 355: 41-46, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34800614

RESUMEN

Impairment of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) is associated with neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and manganism, a neurological disorder caused by overexposure to manganese (Mn) which shares the features of sporadic PD. Mechanisms of Mn-induced neurotoxicity include dysregulation of EAAT2 following activation of the transcription factor Yin Yang 1 (YY1) by transcriptional upregulation, but the posttranslational mechanisms by which YY1 is activated to repress EAAT2 remain to be elucidated. In the present study, we tested if Mn activates YY1 through posttranslational phosphorylation in cultured H4 human astrocytes, leading to EAAT2 repression. The results demonstrate that Mn exposure induced phosphorylation of YY1 at serine residues via kinases Aurora B kinase (AurkB) and Casein kinase II (CK2), leading to YY1 nuclear translocation, YY1/HDAC interactions, binding to the EAAT2 promoter, and consequent decreases in EAAT2 promoter activity and mRNA/protein levels. Although further studies are warranted to fully elucidate the mechanisms of Mn-induced YY1 phosphorylation and resultant EAAT2 impairment, our findings indicate that serine phosphorylation of YY1 via AurkB and CK2 is critical, at least in part, to its activation and transcriptional repression of EAAT2.


Asunto(s)
Astrocitos/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Manganeso/farmacología , Factor de Transcripción YY1/metabolismo , Secuencia de Aminoácidos , Astrocitos/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Línea Celular , Quinasa de Punto de Control 2/genética , Quinasa de Punto de Control 2/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Humanos , Fosforilación , Serina/química , Factor de Transcripción YY1/genética
4.
Sci Rep ; 11(1): 17444, 2021 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-34465813

RESUMEN

Glioblastoma multiforme (GBM) is the most frequent type of primary astrocytomas. We examined the association between single nucleotide polymorphisms (SNPs) in Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC) and Polo-like kinase 1 (PLK1) mitotic checkpoint genes and GBM risk by qPCR genotyping. In silico analysis was performed to evaluate effects of polymorphic biological sequences on protein binding motifs. Chi-square and Fisher statistics revealed a significant difference in genotypes frequencies between GBM patients and controls for AURKB rs2289590 variant (p = 0.038). Association with decreased GBM risk was demonstrated for AURKB rs2289590 AC genotype (OR = 0.54; 95% CI = 0.33-0.88; p = 0.015). Furthermore, AURKC rs11084490 CG genotype was associated with lower GBM risk (OR = 0.57; 95% CI = 0.34-0.95; p = 0.031). Bioinformatic analysis of rs2289590 polymorphic region identified additional binding site for the Yin-Yang 1 (YY1) transcription factor in the presence of C allele. Our results indicated that rs2289590 in AURKB and rs11084490 in AURKC were associated with a reduced GBM risk. The present study was performed on a less numerous but ethnically homogeneous population. Hence, future investigations in larger and multiethnic groups are needed to strengthen these results.


Asunto(s)
Aurora Quinasa A/genética , Aurora Quinasa B/genética , Aurora Quinasa C/genética , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular/genética , Glioblastoma/patología , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Genotipo , Glioblastoma/genética , Humanos , Puntos de Control de la Fase M del Ciclo Celular , Masculino , Persona de Mediana Edad , Pronóstico , Adulto Joven , Quinasa Tipo Polo 1
5.
J Med Chem ; 64(11): 7312-7330, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34009981

RESUMEN

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-myc/metabolismo , Pirimidinas/química , Animales , Aurora Quinasa A/metabolismo , Aurora Quinasa B/antagonistas & inhibidores , Aurora Quinasa B/metabolismo , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Artículo en Inglés | MEDLINE | ID: mdl-32247562

RESUMEN

Bulbus Fritillariacirrhosa D. Don (BFC) has been widely used as an herbal medicament for respiratory diseases in China for over 2000 years. The ethnomedicinal effects of BFC have been scientifically verified, nevertheless its toxicity has not been completely studied. Previously, we have reported that the aqueous extract of BFC induces mitotic aberrations and chromosomal instability (CIN) in human colon epithelial NCM460 cells via dysfunctioning the mitotic checkpoint. Here, we extend this study and specifically focus on the influence of BFC on cytokinesis, the final step of cell division. One remarkable change in NCM460 cells following BFC treatment is the high incidence of binucleated cells (BNCs). More detailed investigation of the ana-telophases reveals that furrow ingression, the first stage of cytokinesis, is inhibited by BFC. Asynchronous cultures treatment demonstrates that furrow ingression defects induced by BFCs are highly associated with the formation of BNCs in ensuing interphase, indicating the BNCs phenotype after BFC treatment was resulted from cytokinesis failure. In line with this, the expression of genes involved in the regulation of furrow ingression is significantly de-regulated by BFC (e.g., LATS-1/2 and Aurora-B are upregulated, and YB-1 is downregulated). Furthermore, long-term treatment of BFC elucidates that the BNCs phenotype is transient and the loss of BNCs is associated with increased frequency of micronuclei and nuclear buds, two biomarkers of CIN. In supporting of these findings, the Nin Jiom Pei Pa Koa and Chuanbei Pipa Gao, two commercially available Chinese traditional medicines containing BFC, are able to induce multinucleation and CIN in NCM460 cells. Altogether, these data provide the first in vitro experimental evidence linking BFC to cytokinesis failure and suggest the resultant BNCs may be intermediates to produce CIN progenies.


Asunto(s)
Inestabilidad Cromosómica/efectos de los fármacos , Citocinesis/efectos de los fármacos , Fritillaria/química , Extractos Vegetales/farmacología , Aurora Quinasa B/genética , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/genética , Inestabilidad Cromosómica/genética , Colon/efectos de los fármacos , Colon/patología , Citocinesis/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mitosis/efectos de los fármacos , Extractos Vegetales/química , Raíces de Plantas/química , Proteínas Serina-Treonina Quinasas/genética , Proteína 1 de Unión a la Caja Y/genética
7.
Bioorg Med Chem Lett ; 30(3): 126885, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31862411

RESUMEN

In order to explore novel Aurora kinase inhibitors, a series of novel 2,4-disubstituted pyrimidines were designed, synthesized and evaluated their in vitro anti-proliferative activities against a panel of cancerous cell lines (A549, HCT-116 and MCF-7). Among them, compound 12a showed the moderate to high anti-proliferative activities against A549 (IC50 = 12.05 ± 0.45 µM), HCT-116 (IC50 = 1.31 ± 0.41 µM) and MCF-7 (IC50 = 20.53 ± 6.13 µM) cells, as well as the Aurora A and Aurora B inhibitory activities with the IC50 values of 309 nM and 293 nM, respectively. Furthermore, compound 12a induced apoptosis by upregulated the pro-apoptotic proteins Bax and decreased the anti-apoptotic protein Bcl-xl in HCT-116 cells. Moreover, the molecular docking study showed that compound 12a had good binding modes with Aurora A and Aurora B and the bioinformatics prediction discovered that compound 12a exhibited good drug likeness using SwissADME. Taken together, these results indicated that 12a may be a potential anticancer compound that was worthy of further development as Aurora kinase inhibitor.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Apoptosis/efectos de los fármacos , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Sitios de Unión , Línea Celular Tumoral , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-Actividad , Proteína X Asociada a bcl-2/metabolismo
8.
Cell Cycle ; 18(18): 2281-2292, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31318643

RESUMEN

Oral cancer is the most prevalent subtype of head and neck cancers and arises mainly from squamous cells of the oral cavity. Patients with advanced metastatic disease have poor overall survival resulting primarily from limited treatment options. Recent advances in the understanding of molecular basis of oral tumorigenesis provide an opportunity for identification and validation of new drug targets. The deregulated expression of the Aurora family of mitotic kinases, for example, has been associated with pathogenesis and poor prognosis in oral cancer. Here, we have evaluated the efficacy of the pan-Aurora inhibitor (CCT137690) alone and in combination with different chemotherapeutic and targeted drugs to identify its synergistic partners in oral cancer cell lines (ORL-48 and ORL-115). CCT137690 effectively inhibits Aurora kinases in both the cell lines and displays potent antiproliferative activity towards them. Prolonged treatment of these cells with CCT137690 results in abrogated mitotic spindle formation, misaligned chromosome attachment and polyploidy that ultimately leads to apoptotic cell death. We further identified that inhibitors of EGFR (gefitinib) and PI3-kinase (pictilisib) synergize with CCT137690 to inhibit the proliferation of the oral cancer cell lines. Moreover, we demonstrate that polyethylene glycol-based nanocapsules harboring combinations of CCT137690 with gefitinib or pictilisib inhibit the growth of oral cancer cell lines in 3D spheroid cultures and induce apoptosis that is comparable to free drug combinations. In conclusion, we have demonstrated the in vitro efficacy of CCT137690 in oral cancer cell lines, identified novel drug combinations with CCT137690 and synthesized nanocapsules containing these drug combinations for co-administration.


Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos/métodos , Gefitinib/farmacología , Imidazoles/farmacología , Indazoles/farmacología , Neoplasias de la Boca/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Sulfonamidas/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Neoplasias de la Boca/patología , Nanocápsulas
9.
Integr Cancer Ther ; 18: 1534735418808586, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30428726

RESUMEN

Mulberry fruit water extract (MWE) has been reported to synergistically enhance the cytotoxic effect of paclitaxel by promoting mitotic catastrophe to induce apoptosis in bladder cancer cells in our previous work. The aim of this study was to evaluate and to mechanistically explore the effects of MWE on bladder cancer responses to ionizing radiation (IR) by treating TSGH 8301 bladder carcinoma cells with MWE after exposing to IR. The results of MTT assay showed a synergistic cytotoxicity of IR with the co-treatment of MWE (IR/MWE) by inducing G2/M phase arrest as demonstrated by flow cytometry analysis in TSGH 8301, HT1367 and HT1197 bladder carcinoma cells lines. The IR/MWE-treated cells expressed increased levels of the G2/M phase arrest-related proteins cdc2/cyclin B1 and displayed giant multinucleated morphology, a typical characteristic of mitotic catastrophe. Immunofluorescent confocal microscopy revealed that the combined strategy inhibited Aurora B phosphorylation through Ras/Raf/MEK/ERK signaling cascade as demonstrated by Western blotting analysis. IR/MWE also caused an inhibitory effect on Plk1 and the subsequent downstream regulator RhoA repression and Cep55 induction, which would influence cell cycle progression in the early steps of cytokinesis. A profound tumor growth suppression and inactivation of Aurora B activity in the tumor tissues by IR/MWE treatment were confirmed in the TSGH 8301 xenograft model in vivo. These data demonstrated that MWE could be an effective auxiliary to synergize with radiation on the anticancer efficacy by promoting mitotic catastrophe through inhibition of Aurora B, providing a novel and effective therapeutic option for bladder cancer management.


Asunto(s)
Aurora Quinasa B/antagonistas & inhibidores , Frutas/química , Mitosis/efectos de los fármacos , Morus/química , Extractos Vegetales/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/radioterapia , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fase G2/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Radiación Ionizante , Transducción de Señal/efectos de los fármacos , Agua/química
10.
Biomed Res Int ; 2017: 2320519, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29201898

RESUMEN

Platelets (PLTs) are produced by megakaryocytes (MKs) that completed differentiation and endomitosis. Endomitosis is an important process in which the cell replicates its DNA without cytokinesis and develops highly polyploid MK. In this study, to gain a better PLTs production, four small molecules (Rho-Rock inhibitor (RRI), nicotinamide (NIC), Src inhibitor (SI), and Aurora B inhibitor (ABI)) and their combinations were surveyed as MK culture supplements for promoting polyploidization. Three leukemia cell lines as well as primary mononuclear cells were chosen in the function and mechanism studies of the small molecules. In an optimal culture method, cells were treated with different small molecules and their combinations. The impact of the small molecules on megakaryocytic surface marker expression, polyploidy, proliferation, and apoptosis was examined for the best MK polyploidization supplement. The elaborate analysis confirmed that the combination of SI and RRI together with our MK induction system might result in efficient ploidy promotion. Our experiments demonstrated that, besides direct downregulation on the expression of cytoskeleton protein actin, SI and RRI could significantly enhance the level of cyclins through the suppression of p53 and p21. The verified small molecule combination might be further used in the in vitro PLT manufacture and clinical applications.


Asunto(s)
Aurora Quinasa B/genética , Plaquetas/metabolismo , Megacariocitos/metabolismo , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Actinas/genética , Aurora Quinasa B/antagonistas & inhibidores , Plaquetas/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Megacariocitos/efectos de los fármacos , Niacinamida/administración & dosificación , Poliploidía , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteína p53 Supresora de Tumor/genética , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Proteínas de Unión al GTP rho/genética , Familia-src Quinasas/antagonistas & inhibidores
11.
Biomed Pharmacother ; 90: 402-413, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28390310

RESUMEN

The infrequent manifestation of SIRT1 and Aurora B kinase has shown to play a pivotal role in colorectal cancer (CRC) progression by regulating Wnt signaling pathway. The present study investigates the signaling events that regulate the modulation of SIRT1 and Aurora B kinase expression and it's mediated cell proliferation in SW480 human primary adenocarcinoma CRC cells using Butea monosperma floral compounds (BMFC). In this, cell viability, mitochondrial mediated apoptosis, cell cycle arrest and inhibition of Wnt pathway were examined. Interestingly, the active novel compound, sodium salt of butrin, from BMFC significantly enhances the apoptosis activity, where SIRT1 and Aurora B kinase were ectopically overexpressed in CRC cells. Moreover, mRNA and protein expressions analysis indicates that the expression of GSK-3ß, ß-catenin, cyclin D1, pAKT, TGF-3ß, SIRT1 and Aurora B kinase were down regulated in BMFC treated cells. These findings provide valuable information that the active BMFC having great impact on SIRT1 and Aurora B kinase mediated Wnt signaling down regulation in SW480 CRC cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Aurora Quinasa B/metabolismo , Butea/química , Neoplasias Colorrectales/tratamiento farmacológico , Flavonoides/farmacología , Flores/química , Sirtuina 1/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Ciclina D1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , ARN Mensajero/metabolismo , Sodio/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo
12.
Proc Natl Acad Sci U S A ; 113(50): 14366-14371, 2016 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-28182563

RESUMEN

X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.


Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Metilación de ADN/efectos de los fármacos , Inactivación del Cromosoma X/efectos de los fármacos , Animales , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Aurora Quinasa B/antagonistas & inhibidores , Aurora Quinasa B/genética , Aurora Quinasas/genética , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azepinas/administración & dosificación , Línea Celular , Decitabina , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Técnicas de Silenciamiento del Gen , Genes Ligados a X , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ensayos Analíticos de Alto Rendimiento , Ratones , Ratones Transgénicos , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Cromosoma X/efectos de los fármacos , Cromosoma X/genética
13.
Food Funct ; 6(12): 3746-59, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26369427

RESUMEN

Eriocaulon sieboldianum (Sieb. & Zucc. ex Steud.) is an edible and medicinal plant used in traditional Chinese medicine. Often in combination with other herbs, it is processed into healthcare beverages for expelling wind-heat, protecting eyes, and reducing blood lipids. Besides, its water decoction together with other herbs has been utilized to treat cancer in China. However, the active ingredients and the precise cellular mechanisms of E. sieboldianum remain to be elucidated. The Aurora kinase family plays critical roles in the regulation of cell division and has attracted great attention to the identification of small-molecule Aurora kinase inhibitors for potential treatment of cancer. A molecular docking study was employed for docking of the most bioactive compounds. Hispidulin (HPDL) and quercetin-3-O-(6''-O-galloyl)-ß-D-galactopyranoside (QGGP) were singled out as potent inhibitors of Aurora kinase. Their inhibitory activity towards Aurora kinase was further confirmed by the obvious decrease in autophosphorylation of Aurora-A (Thr288) and Aurora-B (Thr232). Moreover, the induction of cell cycle arrest in HepG2 cells and the suppressed phosphorylation of histone H3 were also consistent with the inhibition of Aurora kinase. The data indicate that the E. sieboldianum extract and its two active compounds, HPDL and QGGP, could effectively induce apoptosis via p53, MAPKs and the mitochondrial apoptotic pathways. These findings could improve the understanding and enhance the development of drugs based on E. sieboldianum and raise its application value in anticancer therapy or prevention. In addition, our results indicated that Aurora kinase might be a novel target of HPDL and QGGP.


Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Eriocaulaceae/química , Extractos Vegetales/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/metabolismo , Aurora Quinasa B/antagonistas & inhibidores , Aurora Quinasa B/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , China , Flavonas/farmacología , Galactósidos/farmacología , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacología , Células Hep G2 , Humanos , Fosforilación , Extractos Vegetales/química , Quercetina/análogos & derivados , Quercetina/farmacología
14.
Bioorg Med Chem Lett ; 25(15): 2937-42, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26048792

RESUMEN

Aurora B kinase plays an important role in the cell normal mitosis and overexpresses in a variety of tumors. Inhibition of Aurora B kinase resulted in an apoptosis of cancer cells, which prevented tumor growth in xenograft models. In this Letter, we developed a luminescent kinase assay to perform high-throughput screening for identification of small molecule Aurora B inhibitors. Two 3,5,6-substituted indolin-2-one derivatives were identified within an in-house compound library. Their new derivatives were then designed and synthesized that resulting two new inhibitors of Aurora B kinase with improved potency. Docking simulation further demonstrated the proposed binding modes between indolin-2-one inhibitor and Aurora B.


Asunto(s)
Aurora Quinasa B/antagonistas & inhibidores , Pruebas de Enzimas/métodos , Indoles/química , Indoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Secuencia de Aminoácidos , Aurora Quinasa B/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Humanos , Mediciones Luminiscentes/métodos , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Péptidos/química , Péptidos/metabolismo
15.
Bioorg Med Chem ; 22(21): 5813-23, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25270403

RESUMEN

Two series of 20 novel 4-aminoquinazoline-urea derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activity against six human cancer cell lines (K562, U937, A549, NCI-H661, HT29 and LoVo) using the MTT-based assay. Most compounds showed significant antiproliferative activities against four solid tumor cell lines, but no or poor activities against two leukemia cell lines. Furthermore, the target compounds were screened for Aurora A/B kinases inhibitory activity. Among them, 7c, 7d, 8c, and 8d are more potent against Aurora A kinase than ZM447439. Docking study of compounds 7d and ZM447439 revealed that they bound strongly to the ATP-binding sites of Aurora A and B. Thus, they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting Aurora kinases.


Asunto(s)
Antineoplásicos/química , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Quinazolinas/química , Urea/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Benzamidas/química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Relación Estructura-Actividad
16.
Artículo en Inglés | MEDLINE | ID: mdl-24680981

RESUMEN

Fisetin, a plant flavonol commonly found in fruits, nuts and vegetables, is frequently added to nutritional supplements due to its reported cardioprotective, anti-carcinogenic and antioxidant properties. Earlier reports from our laboratory and others have indicated that fisetin has both aneugenic and clastogenic properties in cultured cells. More recently, fisetin has also been reported to target Aurora B kinase, a Ser/Thr kinase involved in ensuring proper microtubule attachment at the spindle assembly checkpoint, and an enzyme that is overexpressed in several types of cancer. Here we have further characterized the chromosome damage caused by fisetin and compared it with that induced by two known Aurora kinase inhibitors, VX-680 and ZM-447439, in cultured TK6 cells using the micronucleus assay with CREST staining as well as a flow cytometry-based assay that measures multiple types of numerical chromosomal aberrations. The three compounds were highly effective in inducing aneuploidy and polyploidy as evidenced by increases in kinetochore-positive micronuclei, hyperdiploidy, and polyploidy. With fisetin, however, the latter two effects were most significantly observed only after cells were allowed to overcome a cell cycle delay, and occurred at higher concentrations than those induced by the other Aurora kinase inhibitors. Modest increases in kinetochore-negative micronuclei were also seen with the model Aurora kinase inhibitors. These results indicate that fisetin induces multiple types of chromosome abnormalities in human cells, and indicate a need for a thorough investigation of fisetin-augmented dietary supplements.


Asunto(s)
Aurora Quinasa B/antagonistas & inhibidores , Benzamidas/farmacología , Flavonoides/farmacología , Micronúcleos con Defecto Cromosómico/inducido químicamente , Piperazinas/farmacología , Poliploidía , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Línea Celular , Cromosomas Humanos/genética , Cromosomas Humanos/metabolismo , Flavonoles , Humanos
17.
ChemMedChem ; 9(1): 217-32, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24273104

RESUMEN

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/análogos & derivados , Urea/análogos & derivados , Animales , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células HCT116 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Naftiridinas/química , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacología
18.
J Biomol Screen ; 18(2): 219-25, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22983166

RESUMEN

The Aurora kinases are a group of serine/threonine protein kinases that regulate key steps during mitosis, and deregulation of these proteins (e.g., by gene amplification or overexpression) has been linked to a wide variety of tumor types. Thus, Aurora-A and Aurora-B have been intensely studied as targets for anticancer therapy and are now clinically validated targets. Here we report on the development of a novel fluorescence intensity binding assay for Aurora-A kinase inhibitors using a fluorescently labeled probe compound that shows intramolecular quenching when unbound but exhibits a dramatic increase in fluorescence when bound to Aurora-A.


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Espectrometría de Fluorescencia/métodos , Aurora Quinasa B , Aurora Quinasas , Unión Competitiva/efectos de los fármacos , Línea Celular , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Ligandos , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo
19.
PLoS One ; 7(11): e50645, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23226345

RESUMEN

Yin Yang 1 (YY1) is a ubiquitously expressed and highly conserved multifunctional transcription factor that is involved in a variety of cellular processes. Many YY1-regulated genes have crucial roles in cell proliferation, differentiation, apoptosis, and cell cycle regulation. Numerous mechanisms have been shown to regulate the function of YY1, such as DNA binding affinity, subcellular localization, and posttranslational modification including phosphorylation. Polo-like kinase 1(Plk1) and Casein kinase 2α (CK2 α) were the first two kinases identified to phosphorylate YY1. In this study, we identify a third kinase. We report that YY1 is a novel substrate of the Aurora B kinase both in vitro and in vivo. Serine 184 phosphorylation of YY1 by Aurora B is cell cycle regulated and peaks at G2/M and is rapidly dephosphorylated, likely by protein phosphatase 1 (PP1) as the cells enter G1. Aurora A and Aurora C can also phosphorylate YY1 in vitro, but at serine/threonine residues other than serine 184. We present evidence that phosphorylation of YY1 in the central glycine/alanine (G/A)-rich region is important for DNA binding activity, with a potential phosphorylation/acetylation interplay regulating YY1 function. Given their importance in mitosis and overexpression in human cancers, Aurora kinases have been identified as promising therapeutic targets. Increasing our understanding of Aurora substrates will add to the understanding of their signaling pathways.


Asunto(s)
División Celular , Fase G2 , Proteínas Serina-Treonina Quinasas/metabolismo , Factor de Transcripción YY1/metabolismo , Acetilación , Secuencia de Aminoácidos , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasa C , Aurora Quinasas , ADN/metabolismo , Regulación Enzimológica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Ratones , Mitosis , Fosforilación , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Serina/metabolismo , Transcripción Genética , Factor de Transcripción YY1/química
20.
Cancer Res ; 70(23): 9846-54, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20935223

RESUMEN

In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adulto , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Benzamidas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Células HCT116 , Células HeLa , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Mutación , Neoplasias/enzimología , Neoplasias/patología , Organofosfatos/farmacología , Paclitaxel/farmacología , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/farmacología , Quinazolinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
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