RESUMEN
PURPOSE: Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer. METHODS: In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target. RESULTS: In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 µM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression. CONCLUSION: Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas del Citoesqueleto , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones SCID , Terapia Molecular Dirigida/métodos , Quinasas Relacionadas con NIMA , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI(50) = 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI(50) > 10 µmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Terapia Molecular Dirigida , Niacinamida/análogos & derivados , Proteínas Nucleares/genética , Tiazoles/administración & dosificación , Animales , Apoptosis/genética , Neoplasias de la Mama/patología , Proteínas del Citoesqueleto , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Técnicas In Vitro , Células MCF-7 , Ratones , Niacinamida/administración & dosificación , Proteínas Nucleares/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The hepatitis C virus (HCV) genomic database is expanding rapidly. AIMS: There is a need to provide an updated phylogenetic tree analysis based on the complete coding region of HCV. METHODS: All available HCV complete genome sequences in the HCV databases available through October 2010 were analyzed. RESULTS: The assignment of all known complete sequences up-to-date confirmed the previous six major genotypes and one new sequence, which have been provisionally assigned as subtype 7a. New recombinant forms of HCV, although uncommon, have been detected and were found to have different crossover points. CONCLUSION: This updated analysis based on the complete region of HCV confirmed the validity of the previously assigned genotypes/subtypes and provided an up-to-date reference for future basic research and clinical studies.
Asunto(s)
Genes Virales , Hepacivirus/genética , ARN Viral/genética , Bases de Datos Factuales , Genoma Viral , Genotipo , Hepacivirus/clasificación , FilogeniaRESUMEN
OBJECTIVES: The aim of this study is to determine whether amitotic division or nuclear proliferation is involved in the formation of giant cells (GCs) in giant cell hepatitis (GCH). PATIENTS AND METHODS: Liver sections from 18 pediatric patients with idiopathic infantile GCH and 12 patients with postinfantile GCH were evaluated for the expression of proliferating cell nuclear antigen (PCNA) and human histone 3 (H3) mRNA, transforming growth factor-alpha (TGF-α), TGF-ß1, hepatocyte growth factor (HGF), and epidermal growth factor receptor (EGFR). RESULTS: Proliferation markers were detected in 1% to 80% in the nuclei of GC and non-GC hepatocytes in 10 of 18 (56%) infantile GCH biopsies and 11 of 12 (92%) postinfantile GCH biopsies, but not in normal liver. The expression of proliferation markers in GCs paralleled that in non-GC hepatocytes (P < 0.05 for both markers). TGF-α and EGFR were detected in both GCs (9/29 and 4/30 patients with infantile or postinfantile GCH, respectively) and non-GC hepatocytes (15/29 and 11/30 patients with infantile or postinfantile GCH, respectively). TGF-ß1 and HGF were detected mainly in sinusoidal cells in 20 of 29 and 10 of 30 patients with infantile or postinfantile GCH, respectively; the expression of HGF was positively correlated with PCNA and H3 mRNA in non-GC hepatocytes and with H3 mRNA in GCs (P < 0.01). CONCLUSIONS: Hepatic expressions of nuclear proliferation markers and growth factors were similar in infantile and postinfantile GCH, nuclear proliferation markers were detected in both GCs and non-GC hepatocytes in a high proportion of patients, and expression of HGF correlated positively with the proliferation markers. These data indicate that nuclear proliferation may contribute to the pathogenesis of GCs in at least a proportion of patients with GCH. A model for the pathogenesis of GCH is proposed.
Asunto(s)
Proliferación Celular , Células Gigantes/metabolismo , Hepatitis/metabolismo , Hepatitis/patología , Hepatocitos/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Biomarcadores/metabolismo , Biopsia , Niño , Receptores ErbB/metabolismo , Femenino , Células Gigantes/patología , Factor de Crecimiento de Hepatocito/metabolismo , Hepatocitos/patología , Histonas/genética , Histonas/metabolismo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/metabolismo , ARN Mensajero/metabolismo , Pruebas Serológicas , Estadísticas no Paramétricas , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The expressions of c-Src and focal adhesion kinase (FAK) were studied in 65 Chinese patients with hepatocellular carcinoma (HCC) by immunohistochemistry using rabbit monoclonal antibodies. Expressions of total Src, an active form of Src, and FAK were found in 44/65 (67.7%), 36/45 (55.4%), and 33/56 (58.9%) HCC cases, respectively. There was a good correlation between the expression of total Src, active form of Src, and FAK in these HCC cases (P < 0.001). Expression of Src was not correlated to any clinical parameters, cancer cell phenotypic markers, and pathologic features apart from a positive correlation with alpha-fetoprotein (P < 0.01). The expression of FAK was correlated with earlier onset and the expression of Ki-67 but not proliferating cell nuclear antigen (PCNA) in these HCC cases. Four liver-cancer-derived cell lines (three derived from HCC and one from hepatoblastoma) were then tested with inhibitors against Src. A small molecule, KX2-391, designed to target the substrate binding pocket of Src, was found to have more broad-spectrum activity and better potency than Dasatinib, an adenosine triphosphate (ATP)-competitive inhibitor in vitro. Our data indicates that Src and FAK expression are both elevated and active in Chinese patients with HCC and that Src may play a key role in supporting HCC progression. Src antagonism with specific inhibitors may be an attractive treatment paradigm for patients with HCC.