Humans ; Ovarian Neoplasms/drug therapy* ; Folate Receptor 1/metabolism* ; Female ; Immunohistochemistry/standards* ; Consensus ; Biomarkers, Tumor/metabolism* ; Fallopian Tube Neoplasms/pathology*

PURPOSE: 14-3-3ζ regulates cell signaling, cell cycle progression, and apoptosis, and its overexpression is associated with disease recurrence and poor clinical outcomes in some solid tumors. However, its clinicopathological role in ovarian cancer is unknown. Our goal was to investigate whether 14-3-3ζ is associated with ovarian cancer prognosis. MATERIALS AND METHODS: We examined 14-3-3ζ expression by immunohistochemistry in ovarian cancer tissues obtained from 88 ovarian cancer patients. The examined tissues were of various histologies and stages. 14-3-3ζ expression was also analyzed by western blot in seven ovarian cancer cell lines and a primary ovary epithelial cell line. Cell viability was measured using an MTS-based assay following cisplatin treatment. RESULTS: Among the ovarian cancer samples, 53.4% (47/88) showed high 14-3-3ζ expression, and 14-3-3ζ overexpression was positively correlated with more advanced pathologic stages and grades. 14-3-3ζ overexpression was also significantly associated with poor disease-free survival (DFS) and overall survival (OS) of ovarian cancer patients. Median DFS and OS were 1088 and 3905 days, respectively, in the high 14-3-3ζ expression group, but not reached in the low 14-3-3ζ expression group (p=0.004 and p=0.033, log-rank test, respectively). Downregulating 14-3-3ζ by RNA interference in ovarian cancer cells led to enhanced sensitivity to cisplatin-induced cell death. CONCLUSION: 14-3-3ζ overexpression might be a potential prognostic biomarker for ovarian cancer, and the inhibition of 14-3-3ζ could be a therapeutic option that enhances the antitumor activity of cisplatin.
14-3-3 Proteins/metabolism ; Adult ; Aged ; Cell Line, Tumor ; Cisplatin/therapeutic use ; Disease-Free Survival ; Down-Regulation ; Female ; Gene Knockdown Techniques ; Gene Silencing ; Humans ; Immunohistochemistry ; Middle Aged ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Prognosis ; Young Adult

PURPOSE: This study aimed to investigate whether Mullerian inhibiting substance (MIS) in combination with calcitriol modulates proliferation and apoptosis of human ovarian cancer (OCa) cell lines (SKOV3, OVCAR3, and OVCA433) and identify the signaling pathway by which MIS mediates apoptosis. MATERIALS AND METHODS: OCa cell lines were treated with MIS in the absence or presence of calcitriol. Cell viability and proliferation were evaluated using the Cell Counting Kit-8 assay and apoptosis was evaluated by DNA fragmentation assay. Western blot and enzyme-linked immunosorbent assay were used to determine the signaling pathway. RESULTS: The cells showed specific staining for the MIS type II receptor. Treatment of OCa cells with MIS and calcitriol led to dose- and time-dependent inhibition of cell growth and survival. The combination treatment significantly suppressed cell growth, down-regulated the expression of B-cell lymphoma 2 (Bcl-2), and up-regulated the expressions of Bcl-2 associated X protein, caspase-3, and caspase-9 through the extracellular signal-regulated kinase signaling pathway. CONCLUSION: These results, coupled with a much-needed decrease in the toxic side effects of currently employed therapeutic agents, provide a strong rationale for testing the therapeutic potential of MIS, alone or in combination with calcitriol, in the treatment of OCa.
Anti-Mullerian Hormone/*pharmacology ; Apoptosis/*drug effects ; Calcitriol/*pharmacology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; DNA Fragmentation/*drug effects ; Enzyme-Linked Immunosorbent Assay ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Growth Inhibitors/metabolism/pharmacology ; Humans ; Ovarian Neoplasms/*drug therapy/metabolism/*pathology ; Receptors, Peptide ; Receptors, Transforming Growth Factor beta ; Signal Transduction/*drug effects

OBJECTIVETo investigate the effect of estrogen (E2), progesterone(P4), and paclitaxel (taxol) on the growth of primary human ovarian cancer cells in vitro and the expression of Drosha.

METHODSHuman ovarian cancer cells were treated with estrogen, progesterone or in combination with paclitaxel in vitro. The inhibition rate of ovarian cancer cells was assessed by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis rate and cell cycle were determined by FACS analysis. The relative abundence of Drosha expression was detected by real-time quantitative PCR (qRT-PCR) and Western blotting.

RESULTSThe inhibition rate of the estrogen group, progesterone group, paclitaxel group, E2(+)Taxol group, P4(+)Taxol group was (31.53 ± 8.21)%, (25.22 ± 15.50)%, (46.71 ± 4.25)%, (69.46 ± 3.71)%, and (47.35 ± 39.02)%, respectively, significantly higher than that of the control group (0%, P<0.05 for all). Relative to the ER (-) in ovarian cancer cells,Drosha mRNA expression level of estrogen group, progesterone group, paclitaxel group, E2(+) Taxol group,and P4(+)Taxol group was 1.62 ± 0.10,1.60 ± 0.10,1.75 ± 0.16,1.95 ± 0.20, and 1.53 ± 0.06, respectively, significantly higher than that of the control group (1.00, P<0.05 for all). Relative to the ER (+)in ovarian cancer cells,the Drosha mRNA expression level of estrogen group, progesterone group, paclitaxel group, E2(+)taxol group, and P4(+)Taxol group was 1.03 ± 0.14, 1.60 ± 0.09, 1.75 ± 0.16, 1.60 ± 0.10, 1.53 ± 0.06, respectively except estrogen group, significantly higher than that of the control group (1.00, P<0.05). Relative to the ER (-) in ovarian cancer cells, the Drosha protein expression levels of the control group, estrogen group, progesterone group, paclitaxel group, E2(+) taxol group, and P4(+) Taxol group were 0.25 ± 0.05, 0.87 ± 0.30, 0.85 ± 0.38, 1.30 ± 0.21, 1.75 ± 0.83, 1.62 ± 0.82, respectively, with a significant difference between the experimental groups and the control group (P<0.05). Relative to the ER(+)ovarian cancer cells, the Drosha protein expression levels in the estrogen group, progesterone group, paclitaxel group, E2(+) taxol group, and P4(+) taxol group, were 0.28 ± 0.16, 0.85 ± 0.38, 1.30 ± 0.21, 0.94 ± 0.18, and 1.62 ± 0.82, respectively except estrogen group, significantly higher than that of the control group (0.25 ± 0.05, P<0.05 for all).

CONCLUSIONSEstrogen and progesterone in combination with paclitaxel can inhibit the growth of human ovarian cancer cells in vitro, and affect the cell apoptosis rate. Estrogen and taxol can alter the cell cycle. Estrogen and progesterone combined with paclitaxel show tumor suppressing or sensitizing effect through upregulated Drosha expression, and are associated with the estrogen receptor expression.

Antineoplastic Agents, Phytogenic ; pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Apoptosis ; Cell Cycle ; Cell Growth Processes ; drug effects ; Cell Line, Tumor ; Coloring Agents ; Drug Therapy, Combination ; Estrogens ; pharmacology ; Female ; Humans ; In Vitro Techniques ; Ovarian Neoplasms ; chemistry ; drug therapy ; metabolism ; pathology ; Paclitaxel ; pharmacology ; Progesterone ; pharmacology ; RNA, Messenger ; metabolism ; Receptors, Estrogen ; metabolism ; Ribonuclease III ; genetics ; metabolism ; Tetrazolium Salts ; Thiazoles ; Up-Regulation

PURPOSE: To investigate chemosensitivity with an adenosine triphosphate-based chemotherapy response assay in patients with epithelial ovarian or peritoneal cancer according to tumor histology, grade, and disease status. MATERIALS AND METHODS: One hundred specimens were collected during primary or secondary debulking from 67 patients with primary ovarian cancer, 24 patients with recurrent ovarian cancer, 5 patients with primary peritoneal cancer, and 4 patients with recurrent peritoneal cancer; samples were collected between August 2006 and June 2009. Tumor cells were isolated and cultured for 48 hours in media containing chemotherapy. The chemosensitivity index (CI) was calculated as 300 minus the sum of the cell death rate at 0.2x, 1x, and 5x drug concentrations, and the CI values were compared. RESULTS: CI values were obtained from 93 of 100 patients. The most active agents against primary disease were ifosfamide and paclitaxel. For primary serous adenocarcinoma, paclitaxel and irinotecan were the most active, followed by ifosfamide. For clear cell carcinoma, ifosfamide was the most active, followed by paclitaxel and irinotecan. Although not statistically significant, the CIs of cisplatin, carboplatin, paclitaxel, and docetaxel decreased as tumor grade increased. In 14 cases of recurrent disease, paclitaxel was the most active, followed by ifosfamide and cisplatin. CONCLUSION: Ifosfamide and paclitaxel were the most active drugs for primary and recurrent disease. Therefore, we recommend further clinical studies to confirm the efficacy of paclitaxel, ifosfamide, and cisplatin combination chemotherapy for recurrent and primary ovarian cancer.
Adenocarcinoma, Clear Cell/*drug therapy/metabolism/pathology ; Adenosine Triphosphate/*metabolism ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Camptothecin/administration & dosage/analogs & derivatives ; Carboplatin/therapeutic use ; Cisplatin/administration & dosage ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor/methods ; Female ; Humans ; Ifosfamide/administration & dosage ; Middle Aged ; Neoplasm Recurrence, Local/*drug therapy ; Neoplasms, Glandular and Epithelial/*drug therapy/metabolism/pathology ; Ovarian Neoplasms/*drug therapy/metabolism/pathology ; Paclitaxel/therapeutic use ; Peritoneal Neoplasms/*drug therapy/metabolism/pathology ; Predictive Value of Tests ; Sensitivity and Specificity ; Taxoids/administration & dosage

OBJECTIVE: Epithelial cell adhesion molecule (EpCAM) has experienced a renaissance lately as a binding site for targeted therapy as well as a prognostic marker in epithelial malignancies. Aim of this study was to study EpCAM as a potential prognostic marker in epithelial ovarian cancer (EOC). METHODS: EpCAM expression was assessed by immunohistochemistry on paraffin-embedded primary EOC-tissue samples. EpCAM overexpression was defined as an expression of EpCAM of 76% to 100%. Tissue samples and clinical data were systematically collected within the international and multicenter "Tumorbank Ovarian Cancer" network. RESULTS: Seventy-four patients, diagnosed with EOC between 1994 and 2009, were included in the study (median age, 56 years; range, 31 to 86 years). The majority of the patients (81.1%) presented with an advanced stage International Federation of Gynecology and Obstetrics (FIGO) III/IV disease. Histology was of the serous type in 41 patients (55.4%), endometrioid in 19 (25.6%), and mucinous in 14 (19%). EpCAM was overexpressed in 87.7%. Serous tumors overexpressed EpCAM significantly more often than mucinous tumors (87.8% vs. 78.6%, p=0.045); while no significant difference was noted between the other histological subgroups. EpCAM overexpression was significantly associated with a better progression free survival and higher response rates to platinum based chemotherapy (p=0.040 and p=0.048, respectively). EpCAM was identified as an independent prognostic marker for overall survival (p=0.022). CONCLUSION: Our data indicate a significant association of EpCAM overexpression with a more favorable survival in EOC-patients. Serous cancers showed a significant EpCAM overexpression compared to mucinous types. Larger multicenter analyses are warranted to confirm these findings.
Adult ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/*metabolism ; Antineoplastic Agents/*therapeutic use ; Carboplatin/therapeutic use ; Cell Adhesion Molecules/*metabolism ; Female ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Neoplasm Proteins/metabolism ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial/*diagnosis/drug therapy/pathology ; Organoplatinum Compounds/*therapeutic use ; Ovarian Neoplasms/*diagnosis/drug therapy/pathology ; Paclitaxel/therapeutic use ; Prognosis ; Tissue Banks ; Treatment Outcome ; Tumor Markers, Biological/*metabolism

12E7 Antigen ; Adnexa Uteri ; surgery ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD ; metabolism ; Cell Adhesion Molecules ; metabolism ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Granulosa Cell Tumor ; drug therapy ; metabolism ; pathology ; surgery ; Humans ; Hysterectomy ; methods ; Inhibins ; metabolism ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Ovarian Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Survival Rate ; Vimentin ; metabolism

Triptolide, a compound extracted from the traditional Chinese medicine preparation of Tripterygium wilfordii Hook F., has been reported to have anti-inflammatory and anti-cancer activities. However, its effect on ovarian cancer invasion is unknown. We observed that MMP7 and MMP19 expression increased in ovarian cancer tissue. Triptolide treatment inhibited the migration and invasion of ovarian cancer cells SKOV3 and A2780 at the concentration of 15 nM. We also observed that triptolide suppressed MMP7 and MMP19 promoter activity in a dose-dependent manner, down-regulating the expressions of these promoters on mRNA and protein level. Moreover, triptolide enhanced E-cadherin expression in ovarian cancer cells. In vivo, triptolide inhibited tumor formation and metastasis in nude mice, and suppressed MMP7 and MMP19 expression; it also enhanced E-cadherin expression in tumor in a dose-dependent manner. Over expression of MMP7 and MMP19, or suppression of E-cadherin expression partially abolished the inhibitory effect of triptolide on invasion of ovarian cancer cells. To summarize, triptolide significantly inhibited the migration and invasion of ovarian cancer cells by suppression of MMP7 and MMP19 and up-regulation of E-cadherin expression. This study shows that triptolide is a good candidate for the treatment of ovarian cancer and reduction of metastasis.
Animals ; Antineoplastic Agents, Alkylating/*pharmacology ; Cadherins/*genetics/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cystadenocarcinoma, Serous/*drug therapy/pathology ; Diterpenes/*pharmacology ; Epoxy Compounds/pharmacology ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Matrix Metalloproteinase 7/genetics/*metabolism ; Matrix Metalloproteinases, Secreted/genetics/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Invasiveness ; Ovarian Neoplasms/*drug therapy ; Paclitaxel/pharmacology ; Phenanthrenes/*pharmacology ; Promoter Regions, Genetic ; Up-Regulation/drug effects ; Xenograft Model Antitumor Assays

OBJECTIVETo observe the gene expression of herpes simplex virus type 1 thymidine kinase (HSVl-tk) in rat malignant ovarian tumor tissues and the therapeutic effect of ganciclovior (GCV) after intra-arterial infusion of HSVl-tk gene therapy mediated by GE7-delivery system.

METHODSA GE7-polylysine/pCMV-HSV1-tk/polylysine-HA20 4-element complex was constructed. Eighteen rats with DMBA-induced ovarian tumor were divided into 3 groups as Atk, ANS and Vtk groups. The 4-element complex GE7-polylysine/pCMV-HSV1-tk/polylysine-HA20 was injected via the ovarian artery into the rats of Atk group, saline buffer was injected in the ANS groups, and the 4-element complex was injected via the tail vein into the rats of Vtk group. All rats received intraperitoneal injection of GCV in a dose of 50 mg/kg daily for 10 days. The rats were sacrificed 3 days after the final dose of GCV, and the tumor weight was measured and tumor growth inhibition rate was calculated. Flow cytometry was used to assess the cell cycle and apoptosis.

RESULTSThe tumor weight in the rats of Atk group was (4.77 ± 2.31) g, significantly lower than that of ANS group [(14.66 ± 6.26) g, P < 0.01] and Vtk group [(17.53 ± 7.19) g, P < 0.01]. The tumor growth inhibition rate of the Atk group was 67.5%, while that of Vtk group was -19.6%. The flow cytometry showed that S-phase tumor cells in the Atk group were (54.32 ± 9.65)%, significantly higher than that in the ANS (27.43 ± 9.22)% and (30.16 ± 11.57)% in the Vtk group (both P < 0.01). The tumor cell apoptosis rate in the Atk group was (39.15 ± 12.16)%, significantly higher than that in the ANS group [(11.86 ± 5.28)%, P < 0.01] and Vtk group [(14.32 ± 6.43)%, P < 0.01].

CONCLUSIONHSV1-tk/GCV gene therapy system mediated by GE7 non-viral delivery system via ovarian arterial infusion effectively causes cell cycle arrest at S phase and enhances cell apoptosis, therefore, exerts an inhibitory effect on tumor growth.

9,10-Dimethyl-1,2-benzanthracene ; Adenocarcinoma ; chemically induced ; pathology ; therapy ; Animals ; Antiviral Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Female ; Ganciclovir ; pharmacology ; Gene Transfer Techniques ; Genetic Therapy ; Herpesvirus 1, Human ; genetics ; metabolism ; Infusions, Intra-Arterial ; Ovarian Neoplasms ; chemically induced ; pathology ; therapy ; Random Allocation ; Rats ; Rats, Wistar ; Thymidine Kinase ; genetics ; metabolism

OBJECTIVETo investigate the clinical features and factors involved in the drug resistance and prognosis of ovarian clear cell adenocarcinoma (OCCA).

METHODSForty-seven OCCA patients and 53 ovarian serous cyst adenocarcinoma (OSCA) patients were included in this study. Their clinical characteristics, drug resistance, and prognostic factors were analyzed.

RESULTSThe onset age of OCCA was (49.09 + 11.80) years old, and that of OSCA was (55.51 + 1.38) year old. There were 53.3% (24/45) of OCCA and 98.0% (50/51) of OSCA patients who had elevated CA125 levels. There were 46.8% (22/47) of OCCA patients and 7.5% (4/53) of OSCA patients who suffered from endometriosis (EMS). The percentage of early stage (stage I and stage II) OCCA was 80.9% (38/47), and that of OSCA was 11.3% (6/53). A statistically significant difference was observed on all these aspects (P < 0.05). The percentage of drug resistant OCCA was 26.1% (12/46), and that of OSCA was 24.0% (12/50), with a non-significant difference (P = 0.814).Among the patients with advanced stage disease, the percentage of drug resistance was 87.5% (7/8) for OCCA, while that of OSCA was 25.0% (11/44), showing a statistically significant difference (P = 0.003). Multiple logistic regression analysis revealed that OCCA (OR = 21.774, 95%CI: 2.438 to 194.431) and advanced stage (OR = 58.329, 95%CI: 5.750 to 591.703) were independent risk factors of drug resistance in ovarian epithelial cancers. For the advanced stage patients, the median overall survival time of OCCA and OSCA were 11 and 29 months, respectively, with a statistically significant difference (P = 0.000). Cox survival analysis showed that OCCA, advanced stage, suboptimal surgery, fewer than 6 cycles of chemotherapy and drug resistance were all risk factors of OS in ovarian cancer patients (P < 0.05).

CONCLUSIONSThe age of onset in OCCA patients is younger than that of OSCA patients. The proportion of combination with endometriosis (EMS) is higher, and more early stage disease is observed in OCCA patients. The percentage of drug resistant in OCCA is higher, especially in advanced stage patients. The prognosis of advanced stage OCCA patients is poorer than that of OSCA patients in advanced stage.

Adenocarcinoma, Clear Cell ; complications ; drug therapy ; metabolism ; pathology ; surgery ; Adult ; CA-125 Antigen ; metabolism ; Cystadenocarcinoma, Serous ; complications ; drug therapy ; metabolism ; pathology ; surgery ; Drug Resistance, Neoplasm ; Endometriosis ; complications ; Female ; Follow-Up Studies ; Humans ; Middle Aged ; Neoplasm Staging ; Ovarian Diseases ; complications ; Ovarian Neoplasms ; complications ; drug therapy ; metabolism ; pathology ; surgery ; Proportional Hazards Models ; Survival Rate