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1.
J Invest Dermatol ; 143(10): 1993-2006.e10, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37003468

RESUMEN

Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice.


Asunto(s)
Aurora Quinasa A , Melanoma , Humanos , Ratones , Animales , Aurora Quinasa A/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Pirimidinonas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Ácidos Grasos , Proteínas Proto-Oncogénicas B-raf/genética , Mutación
2.
Fitoterapia ; 167: 105491, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37001826

RESUMEN

Fractionation of the ethanol extract of Artemisia verlotorum led to the identification of eight undescribed eudesmane-type sesquiterpenoids, artemverlolides A-H (1-8). Their structures were determined by spectral analyses (HRESIMS, 1D and 2D NMR, IR, and ECD). Network pharmacology predicted that compounds 1-8 might be target on AURKA, CCNA2, CYP2C19, and EPHX2 with possibly antihepatoma effect from Swiss TargetPrediction and Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the targets significantly enriched in FoxO signaling pathway. The molecular docking suggested that compound 8 had high binding affinity with AURKA. Furthermore, the interaction between compound 8 and AURKA was determined by Surface Plasmon Resonance (SPR) assay. The result suggested that compound 8 bound to AURKA with KD value of 68.0µM and was consistent with the predicted data, demonstrating that AURKA might be one of acting targets of 8.


Asunto(s)
Artemisia , Carcinoma Hepatocelular , Medicamentos Herbarios Chinos , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamiento farmacológico , Farmacología en Red , Aurora Quinasa A , Simulación del Acoplamiento Molecular , Neoplasias Hepáticas/tratamiento farmacológico , Estructura Molecular
3.
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
4.
Int J Mol Sci ; 22(23)2021 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-34884931

RESUMEN

Neuroblastoma is a severe childhood disease, accounting for ~10% of all infant cancers. The amplification of the MYCN gene, coding for the N-Myc transcription factor, is an essential marker correlated with tumor progression and poor prognosis. In neuroblastoma cells, the mitotic kinase Aurora-A (AURKA), also frequently overexpressed in cancer, prevents N-Myc degradation by directly binding to a highly conserved N-Myc region. As a result, elevated levels of N-Myc are observed. During recent years, it has been demonstrated that some ATP competitive inhibitors of AURKA also cause essential conformational changes in the structure of the activation loop of the kinase that prevents N-Myc binding, thus impairing the formation of the AURKA/N-Myc complex. In this study, starting from a screening of crystal structures of AURKA in complexes with known inhibitors, we identified additional compounds affecting the conformation of the kinase activation loop. We assessed the ability of such compounds to disrupt the interaction between AURKA and N-Myc in vitro, using Surface Plasmon Resonance competition assays, and in tumor cell lines overexpressing MYCN, by performing Proximity Ligation Assays. Finally, their effects on N-Myc cellular levels and cell viability were investigated. Our results identify PHA-680626 as an amphosteric inhibitor both in vitro and in MYCN overexpressing cell lines, thus expanding the repertoire of known conformational disrupting inhibitors of the AURKA/N-Myc complex and confirming that altering the conformation of the activation loop of AURKA with a small molecule is an effective strategy to destabilize the AURKA/N-Myc interaction in neuroblastoma cancer cells.


Asunto(s)
Aurora Quinasa A/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirroles/farmacología , Adenosina Trifosfato/metabolismo , Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/química , Azepinas/metabolismo , Azepinas/farmacología , Benzazepinas/metabolismo , Benzazepinas/farmacología , Sitios de Unión , Unión Competitiva , Línea Celular , Evaluación Preclínica de Medicamentos/métodos , Humanos , Proteína Proto-Oncogénica N-Myc/química , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Pirazoles/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacología , Pirroles/metabolismo , Resonancia por Plasmón de Superficie
5.
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
6.
J Ethnopharmacol ; 279: 114386, 2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34224810

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Esophageal cancer, as a high incidence of gastrointestinal cancer, has an indelible impact on human life and health. The combination of Chinese herbal injections and chemotherapy is commonly applied in the treatment of Esophageal cancer. AIM OF THE STUDY: This study aimed to confirm the clinical advantage of Compound Kushen Injection to treat esophageal cancer and explore its molecular mechanism. METHODS: The network meta-analysis method was used for the clinical evaluation of anti-tumor Chinese herbal injections. Initially, several electronic databases were searched to identify randomized controlled trials regarding Chinese herbal injections to treat esophageal cancer from their inception to September 5, 2020. Then, WinBugs and Stata software was used to calculate and analyze the outcome indicators, including total clinical efficiency, improvement of quality of life and adverse reactions. Furthermore, the surface under the cumulative ranking curve and three-dimensional cluster analysis were used to rank the efficacy and safety of Chinese herbal injections about each outcome. Cell Counting Kit-8 assay was used to observe the effect of Compound Kushen Injection on the proliferation of esophageal cancer cells. Real-Time Quantitative PCR and Western Blot analysis were used to detect the mRNA and protein expression of EGFR and AURKA in ESCA cells. RESULTS: The surface under the cumulative ranking curve of Compound Kushen Injection combined with chemotherapy in total clinical efficiency, quality of life, reduction of nausea and vomiting were ranking at 89.1%, 81.8% and 92.4%, respectively. Compound Kushen Injection was determined as the dominant variety in the treatment of esophageal cancer which can inhibit the proliferation of esophageal cancer cells and downregulate the overexpression of EGFR and AURKA mRNA and protein. CONCLUSION: In this study, network meta-analysis was applied to confirm that Compound Kushen Injection has a curative effect on esophageal cancer and is superior to other anti-tumor Chinese herbal injections. Combined with the network pharmacology and in vitro experiment, the mechanism of Compound Kushen Injection inhibiting the proliferation of esophageal cancer cells by regulating the abnormal expression of EGFR and AURKA was revealed.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Farmacología en Red
7.
Exp Mol Med ; 53(5): 835-847, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-34050264

RESUMEN

Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine.


Asunto(s)
Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Biomarcadores de Tumor , Neoplasias/etiología , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Mutaciones Letales Sintéticas , Animales , Ensayos Clínicos como Asunto , Susceptibilidad a Enfermedades , Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Medicina de Precisión , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
8.
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
9.
Clin Cancer Res ; 27(10): 2712-2722, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33753457

RESUMEN

PURPOSE: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation. PATIENTS AND METHODS: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. RESULTS: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. CONCLUSIONS: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/administración & dosificación , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/administración & dosificación , Inhibidores de las Cinasas Janus/administración & dosificación , Pirimidinas/administración & dosificación , Tacrolimus/administración & dosificación , Animales , Aurora Quinasa A/metabolismo , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Evaluación Preclínica de Medicamentos , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad , Humanos , Inmunofenotipificación , Janus Quinasa 2/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Factor de Transcripción STAT3/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Donantes de Tejidos , Trasplante Homólogo
10.
Gen Comp Endocrinol ; 300: 113617, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32950578

RESUMEN

The mitosis-associated protein aurora kinase A (AURKA) regulates the maturation of germ cells. We have previously reported using transcriptome analysis that AURKA is expressed in yak testes. Although Tibetan sheep possess an immense economic value, their reproductive rate is low. Herein, the expression and functions of AURKA in the hypothalamus-pituitary-testicular (HPT) axis in Tibetan sheep from Tianzhu were investigated. The cDNA sequence of sheep AURKA was cloned and bioinformatics techniques were used to predict its structure. Tissue expression of AURKA was determined by qPCR, immunoblotting, immunostaining, and immunohistochemistry. The AURKA coding sequence was found to be 1218 bp in length, encoding a 405-amino acid polypeptide chain. Furthermore, the highest sequence similarity of AURKA with the corresponding sequence in other species was seen in goat and cattle; the least degree of similarity was seen in the domestic cat. In addition, AURKA expression was elevated in the testes compared to that in the hypothalamus and pituitary (p < 0.01). Moreover, AURKA was mainly localized in the hypothalamic paraventricular nucleus (magnocellular), chromophobe cells of the pituitary, and spermatogenic cells of the testis. These results indicated that AURKA might participate in sheep reproductive regulation, thus providing a reference for the study of AURKA function in the reproductive process of Tibetan sheep from Tianzhu.


Asunto(s)
Aurora Quinasa A/metabolismo , Hipotálamo/enzimología , Hipófisis/enzimología , Ovinos/metabolismo , Testículo/enzimología , Secuencia de Aminoácidos , Animales , Aurora Quinasa A/química , Aurora Quinasa A/genética , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Masculino , Filogenia , Tibet
11.
Integr Cancer Ther ; 19: 1534735420983463, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33349071

RESUMEN

San Huang Decoction (SHD), a Chinese herb formula, has been popularly prescribed in the clinical treatment of patients suffering from breast cancer. The aim of this study was to explore the anti-angiogenic effects of SHD in breast cancer and explain the underlying mechanism. Transwell and Matrigel assays showed that SHD reduced human umbilical vein endothelial cell migration and tubule formation and ELISA and qRT-PCR assays demonstrated its mediation of vascular endothelial growth factor (VEGF) expression. siRNA silencing of aurora kinase A (AURKA) produced results similar to those obtained by inhibition of AURKA with SHD. In addition, a chorioallantoic membrane assay was carried out to directly examine the effect of SHD on breast cancer anti-angiogenesis and immunofluorescence and immunohistochemical staining analysis showed that SHD reduced the expression of CD31, AURKA, and VEGF in a xenograft model. Furthermore, SHD regulated extracellular signal-regulated kinase expression in breast cancer cells, which was examined by western blotting. In conclusion, our findings indicated that SHD treatment mimicked the decrease in tumor neovascularization in breast cancer cells after the siRNA-mediated knockdown of AURKA. Thus, SHD may inhibit tumor angiogenesis in breast cancer by targeting AURKA and downregulating the ERK signaling pathway.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Neoplasias de la Mama , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular
12.
Am J Chin Med ; 48(3): 651-678, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32349518

RESUMEN

Cinobufagin is a Na+/K+-ATPase (NKA) inhibitor with excellent anticancer effects to prolong the survival of patients. The purpose of the present study was to clarify the underlying mechanism of the anticancer effects of cinobufagin using overexpression or inhibition of aurora kinase A (AURKA) signaling. First, high expression of Na+/K+-ATPase alpha 1 subunit (ATP1A1) and AURAK resulted in increased malignant transformation in hepatocellular carcinoma (HCC) patients using the cancer genome atlas (TCGA) data and tissue samples. After treatment with cinobufagin, we successfully screened 202, 249, and 335 changing expression proteins in Huh-7 cells under normal, overexpression, and inhibition of AURKA using tandem mass tags (TMT)-labeled quantitative proteomics coupled to 2D liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatics analysis revealed that these molecules were closely associated with chromosome segregation, DNA damage, and regulation of translation processes. We further confirmed that cinobufagin induced DNA damage and chromosome segregation disorders and suppresses translational processing in oncogenes by decreasing the expression of AURKA, mechanistic target of rapamycin kinase (mTOR), p-mTOR, p-extracellular regulated protein kinases (ERK), eukaryotic translation initiation factor 4E (eIF4E), and p-eIF4E, while increasing the expression of p-eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) (S65, T37, T46, T45) and increasing the interaction between eIF4 and 4E-BP1. Our results suggested that cinobufagin performed an antitumor effects in liver cancer cells by inhibiting the AURKA-mTOR-eIF4E axis.


Asunto(s)
Antineoplásicos Fitogénicos , Aurora Quinasa A/metabolismo , Bufanólidos/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Segregación Cromosómica/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Oncogenes/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Células Tumorales Cultivadas
13.
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
14.
Nutrients ; 11(12)2019 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-31817577

RESUMEN

Curcumin has been used as a traditional medicine and/or functional food in several cultures because of its health benefits including anticancer properties. However, poor oral bioavailability of curcumin has limited its oral usage as a food supplement and medical food. Here we formulated curcumin pellets using a solid dispersion technique. The pellets had the advantages of reduced particle size, improved water solubility, and particle porosity. This pellet form led to an improvement in curcumin's oral bioavailability. Additionally, we used the C-Map and Library of Integrated Network-Based Cellular Signatures (LINCS) Unified Environment (CLUE) gene expression database to determine the potential biological functions of formulated curcumin. The results indicated that, similar to conventional curcumin, the formulated curcumin acted as an NF-κB pathway inhibitor. Moreover, ConsensusPathDB database analysis was used to predict possible targets and it revealed that both forms of curcumin exhibit similar biological functions, including apoptosis. Biochemical characterization revealed that both the forms indeed induced apoptosis of hepatocellular carcinoma (HCC) cell lines. We concluded that the formulated curcumin increases the oral bioavailability in animals, and, as expected, retains characteristics similar to conventional curcumin at the cellular level. Our screening platform using big data not only confirms that both the forms of curcumin have similar mechanisms but also predicts the novel mechanism of the formulated curcumin.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/farmacocinética , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Aurora Quinasa A/efectos de los fármacos , Disponibilidad Biológica , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Sorafenib/administración & dosificación
15.
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
16.
Autophagy ; 15(8): 1376-1390, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30773992

RESUMEN

Patients with triple-negative breast cancer (TNBC) often have a poor prognosis largely due to lack of effective targeted therapy. Using a library of seleno-purines coupled to a high-throughput biochemical enzymatic assays we identified a potent pharmacological enhancer of autophagy (referred herein as SLLN-15) that selectively activated cytostatic macroautophagy/autophagy in TNBC preclinical models. SLLN-15 induced a dose-dependent anti-proliferative activity in the TNBC cell lines MDA-MB-231 and BT-20 via induction of autophagy and autophagic flux. This induction was associated with a selective inhibition of AKT-MTOR signaling. Conversely, rapamycin, a known autophagy inducer and MTOR inhibitor, was unable to duplicate SLLN-15's effect on TNBC cells. Inhibition of autophagy by siRNA-mediated targeting of the autophagy regulators, BECN1, ATG5 and ATG7 or using 3-methyladenine (3-MA), significantly protected against SLLN-15-induced inhibition of cell viability, further supporting that SLLN-15-induced inhibition of cancer cell proliferation was autophagy-dependent. SLLN-15-induced autophagy in TNBC cells was also associated with decreased AURKA expression, decreased AKT phosphorylation and subsequent blockage of the AKT-MTOR pathway. In vivo, oral SLLN-15 revealed a potent anticancer and anti-metastatic activity in mice bearing TNBC. Altogether, this study describes a novel regulator of mammalian autophagy, with potential utility as an experimental therapeutic for TNBCs. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; AURKA: aurora kinase A; AURKB: aurora kinase B; BECN1: beclin 1; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; ERBB2: erb-b2 receptor tyrosine kinase 2; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase 1; PI: propidium iodide; SQSTM1/p62: sequestosome 1; TNBC: triple-negative breast cancer.


Asunto(s)
Autofagia , Citostáticos/farmacología , Progresión de la Enfermedad , Purinas/farmacología , Selenio/farmacología , Neoplasias de la Mama Triple Negativas/patología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aurora Quinasa A/metabolismo , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones SCID , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas c-akt/metabolismo , Purinas/química , Selenio/química , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Mama Triple Negativas/ultraestructura
17.
Phytother Res ; 33(3): 640-650, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30536456

RESUMEN

Gossypin is a flavone extracted from Hibiscus vitifolius, which has been reported to exhibit anti-inflammatory, antioxidant, and anticancer activities. However, the anticancer properties of gossypin and its molecular mechanism of action against gastric cancer have not been fully investigated. In the present study, we report that gossypin is an Aurora kinase A (AURKA) and RSK2 inhibitor that suppresses gastric cancer growth. Gossypin attenuated anchorage-dependent and anchorage-independent gastric cancer cell growth as well as cell migration. Based on the results of in vitro screening and cell-based assays, gossypin directly binds to and inhibits AURKA and RSK2 activities and their downstream signaling proteins. Gossypin decreased S phase and increased G2/M phase cell cycle arrest by reducing the expression of cyclin A2 and cyclin B1 and the phosphorylation of the CDC protein. Additionally, gossypin also induced intrinsic apoptosis by activating caspases and PARP and increasing the expression of cytochrome c. Our results demonstrate that gossypin is an AURKA and RSK2 inhibitor that could be useful for treating gastric cancer.


Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Flavonoides/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Neoplasias Gástricas/patología
18.
Nat Commun ; 9(1): 3212, 2018 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-30097580

RESUMEN

ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we show that ARID1A has a synthetic lethal interaction with aurora kinase A (AURKA) in colorectal cancer (CRC) cells. Pharmacological and genetic perturbations of AURKA selectively inhibit the growth of ARID1A-deficient CRC cells. Mechanistically, ARID1A occupies the AURKA gene promoter and negatively regulates its transcription. Cells lacking ARID1A show enhanced AURKA transcription, which leads to the persistent activation of CDC25C, a key protein for G2/M transition and mitotic entry. Inhibiting AURKA activity in ARID1A-deficient cells significantly increases G2/M arrest and induces cellular multinucleation and apoptosis. This study shows a novel synthetic lethality interaction between ARID1A and AURKA and indicates that pharmacologically inhibiting the AURKA-CDC25C axis represents a novel strategy for treating CRC with ARID1A loss-of-function mutations.


Asunto(s)
Aurora Quinasa A/metabolismo , Neoplasias Colorrectales/genética , Proteínas Nucleares/deficiencia , Transducción de Señal , Mutaciones Letales Sintéticas/genética , Factores de Transcripción/deficiencia , Fosfatasas cdc25/metabolismo , Animales , Apoptosis , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN , Evaluación Preclínica de Medicamentos , Femenino , Fase G2 , Técnicas de Inactivación de Genes , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Mitosis , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética
19.
Cancer Lett ; 431: 64-72, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29807113

RESUMEN

To address the unmet need for effective biomarker-driven targeted therapy for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, we conducted a high-throughput drug screen using 1122 compounds in 13 HPV-positive and 11 matched HPV-negative cell lines. The most effective drug classes were inhibitors of polo-like kinase, proteasomes, histone deacetylase, and Aurora kinases. Treatment with a pan-Aurora inhibitor, danusertib, led to G2M arrest and apoptosis in vitro. Furthermore, danusertib decreased tumor size compared with controls in patient derived xenograft models of HNSCC. To identify biomarkers predicting response, we determined associations between mutations and drug sensitivity. Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora kinase inhibitor-induced apoptosis. We identified Aurora kinase inhibitors as effective and understudied drugs in HNSCC and CESC. This is the first published study to demonstrate that mutations in KMT2D, which are common in many cancers, correlate with drug sensitivity in two independent datasets.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Carcinoma de Células Escamosas/genética , Proteínas de Unión al ADN/genética , Mutación , Proteínas de Neoplasias/genética , Infecciones por Papillomavirus/genética , Animales , Apoptosis , Área Bajo la Curva , Benzamidas/farmacología , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/virología , Ciclo Celular , Línea Celular , Proliferación Celular , Evaluación Preclínica de Medicamentos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trasplante de Neoplasias , Papillomaviridae , Infecciones por Papillomavirus/tratamiento farmacológico , Farmacogenética , Pirazoles/farmacología , Neoplasias del Cuello Uterino
20.
Mol Cells ; 41(5): 444-453, 2018 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-29477140

RESUMEN

Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region. Using Flow cytometry, we found that alisertib induces THP-1 differentiation into monocytes. Furthermore, we found that treatment with the KDM6B inhibitor GSK-J4 perturbed the PMA-mediated differentiation of THP-1 cells. Thus, we discovered the mechanism of AURKA-KDM6B signaling that controls the differentiation of THP-1 cells, which has implications for biotherapy for leukemia.


Asunto(s)
Aurora Quinasa A/fisiología , Regulación Leucémica de la Expresión Génica , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/fisiología , Leucemia Monocítica Aguda/patología , Proteínas de Neoplasias/fisiología , Aurora Quinasa A/antagonistas & inhibidores , Azepinas/farmacología , Benzazepinas/farmacología , Diferenciación Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Genes Reporteros , Células HEK293 , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/metabolismo , Monocitos/citología , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/fisiología , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirimidinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas Recombinantes/metabolismo , Células THP-1 , Acetato de Tetradecanoilforbol/farmacología , Factor de Transcripción YY1/metabolismo
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