RESUMEN
Drug resistance is a major concern in the successful treatment of ovarian cancer. In the present study we report a combinational drug regime using arsenic trioxide (ATO) and cisplatin (CDDP) to increase therapeutic potentiality in ovarian cancer cells. ATO-mediated growth inhibition and apoptosis in human suspension ovarian cancer COC1 cells were evaluated by MTT assay and annexin V assay using flow cytometry, respectively. cDNA arrays were performed to screen ATO-mediated gene expression. Treatment of COC1 cells with ATO alone resulted in growth inhibition and apoptosis with a dose-and time-dependent fashion; further cDNA arrays showed that 34 genes (23 up-regulated genes and 11 down-regulated genes) may strongly associate with the antiproliferative and pro-apoptotic effects induced by ATO. Furthermore, Chou-Talalay analysis was used to evaluate the combinational effect of ATO and CDDP as well as dose-reduction index (DRI) in a panel of ovarian cancer cells including CDDP-sensitive and -resistant cell lines. The combination index (CI) analysis indicated that the interaction effect of ATO/CDDP exhibited a wide range of synergism in all the adherent ovarian cancer cells (A2780, IGROV-1, SKOV-3, and R182) as well as 0.93 to 0.69 for IC(50) to IC(90) in suspension COC1 cells where CI < 1, =1, and >1, define synergism, additive effect, and antagonism, respectively. More intriguingly, the combination of ATO and CDDP yielded favorable DRIs ranging from 1.23-fold to 13.51-fold dose reduction. These results suggest that ATO and its combination with CDDP present therapeutic potential for ovarian cancer, and deserve further preclinical and clinical studies.
Asunto(s)
Antineoplásicos/farmacología , Arsenicales/farmacología , Cisplatino/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Óxidos/farmacología , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Ováricas/patologíaRESUMEN
Notch signaling pathways play important roles in cell fate and many diseases, including preeclampsia, the dysregulation of which may be the main cause of maternal mortality. This study aimed to investigate the roles of Notch2 and Notch3 in proliferation and invasion in trophoblast cell lines (BeWo and JAR). Small hairpin RNAs targeting Notch2/Notch3 and Notch2/Notch3-overexpression vectors were designed, constructed and transfected into BeWo and JAR cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were then used to detect Notch2 and Notch3 mRNA and protein levels, and confirm the efficiency of silence and overexpression. Flow cytometry assays were conducted to evaluate the cell cycle of the two cell lines, and transwell assays were used to detect migration and invasion. Western blot analysis was also performed to show the alteration of the cell lines' physiological activities at protein level.When Notch2 was downregulated in BeWo cells, proliferation was dramatically promoted, while migration and invasion were significantly inhibited. When Notch2 was upregulated in JAR cells, proliferation was inhibited, but migration and invasion were promoted. After overexpression of Notch3 in BeWo cells, proliferation was downregulated, but migration and invasion were both upregulated. By contrast, the silencing of Notch3 expression in JAR cells significantly enhanced proliferation, but suppressed migration and invasion. These data indicated that Notch2 and Notch3 mediate the invasion and migration of BeWo and JAR cells, and may play a potential role in early onset severe preeclampsia.
RESUMEN
OBJECTIVE: To evaluate the pregnancy outcome of women with pulmonary hypertension complicating cardiac disease. METHODS: Clinical data of 61 cases of pregnant women with pulmonary hypertension from Jan 1996 to Aug 2004 were analyzed and they were divided into three groups: 32 cases of slight group [pulmonary hypertension from 30 mm Hg (1 mm Hg = 0.133 kPa) to 49 mm Hg], 23 cases of moderate group (pulmonary hypertension from 50 mm Hg to 79 mm Hg) and 6 cases of severe group (pulmonary hypertension equal to or higher than 80 mm Hg). The types of heart disease, cardiac functional status (New York heart association, NYHA), gestational weeks of pregnancy termination, mode of delivery and outcomes of infants were compared between the groups. RESULTS: (1) The occurrence rate of NYHA class III - IV was 5/6 in severe group. The rate of NYHA class I - II was 72% (23/32) in slight group. (2) The rate of moderate and severe pulmonary hypertension was 53% (11/21) and of NYHA class IV 43% (9/21) in rheumatic heart disease. The rate of slight pulmonary hypertension was 97% (35/36) and NYHA class I - II 81% (29/36) in congenital heart disease. (3) The rate of term delivery was 75% (24/32) and the birth weight was 2744 g on average in slight group. The rate of term delivery was 48% (11/23), preterm labor 35% (8/23), abortion 17% (4/23) in moderate group. The rate of term delivery was 1/6, preterm labor occurred in 3 cases, and abortion in 2 cases in severe group. The rates of neonatal complications between the three groups had no significant difference. (4) Caesarean section rate was 79% (48/61) among all patients. (5) Overall maternal mortality was 2% (1/61). CONCLUSIONS: The rate of heart failure increases gradually with the severity of pulmonary hypertension. The severity of pulmonary hypertension in rheumatic heart disease is higher than in congenital heart disease. The rate of maternal mortality and fetal loss increases in pregnant women with pulmonary hypertension complicating cardiac disease. Perinatal morbidity is higher than normal. Cesarean section is more suitable for those women.
Asunto(s)
Cardiopatías/complicaciones , Hipertensión Inducida en el Embarazo , Hipertensión Pulmonar/complicaciones , Resultado del Embarazo , Aborto Inducido/métodos , Adulto , Cesárea , Femenino , Edad Gestacional , Cardiopatías/patología , Humanos , Hipertensión Inducida en el Embarazo/epidemiología , Hipertensión Inducida en el Embarazo/patología , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/patología , Recién Nacido , Embarazo , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
CONTEXT: Preeclampsia is associated with elevated levels of proinflammatory cytokines, excess decidual macrophages, and dendritic cells. IL-1ß- or TNF-α-stimulated leukocyte-free first trimester decidual cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua. OBJECTIVE: The relative potency of IL-1ß- or TNF-α-induced first trimester decidual cell-secreted chemokines in chemoattracting macrophages or dendritic cells and the signaling pathways involved in the expression of these chemokines were evaluated. INTERVENTIONS AND MAIN OUTCOME MEASURES: First trimester decidual cells were treated with estradiol + medroxyprogesterone acetate ± IL-1ß or TNF-α. The chemotaxis assay was performed by incubating conditioned medium from first trimester decidual cells with neutralizing antibody for six chemokines. The activation of each signaling pathway was examined by Western blotting, flow cytometry, confocal microscopy, and ELISA with or without kinase and nuclear factor κB (NFκB) inhibitors. RESULTS: Neutralization of CCL2 and CCL5 significantly reduced chemotaxis of monocyte and dendritic cells up to 50 and 36%, respectively. NFκB and MAPK (MAPK kinase, JUN NH2-terminal kinase, p38 kinase) pathways were activated by IL-1ß or TNF-α in first trimester decidual cells. In IL-1ß- or TNF-α-stimulated first trimester decidual cells, NFκB inhibitor suppressed production of all six chemokines; JUN NH2-terminal kinase inhibitor inhibited secretion of CCL2, CCL4, and CCL5; and MAPK kinase and p38 inhibitor decreased production of CXCL8. CONCLUSIONS: Up-regulation of CCL2 and CCL5 by first trimester decidual cells in response to proinflammatory stimuli may account for the accumulation of macrophages and dendritic cells in preeclamptic decidua. These chemokines and underlying IL-1ß- or TNF-α-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia.