Science.gov

Sample records for inhibit ovarian cancer

  1. Ormeloxifene efficiently inhibits ovarian cancer growth

    PubMed Central

    Maher, Diane M.; Khan, Sheema; Nordquist, Jordan; Ebeling, Mara C.; Bauer, Nichole A.; Kopel, Lucas; Singh, Man Mohan; Halaweish, Fathi; Bell, Maria C.; Jaggi, Meena; Chauhan, Subhash C.

    2014-01-01

    Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer. PMID:25306892

  2. Lost expression of DCC gene in ovarian cancer and its inhibition in ovarian cancer cells.

    PubMed

    Meimei, Liu; Peiling, Li; Baoxin, Li; Changmin, Li; Rujin, Zhuang; Chunjie, Hu

    2011-03-01

    Ovarian cancer is a leading cause of cancer-related women mortality in China. In recent years, the molecular mechanisms involved in ovarian carcinoma development and/or progression have been intensely studied, and several genes have been identified. Deleted in Colorectal Carcinoma (DCC), is an important tumor suppressor gene, which is inactivated in many kinds of tumors, and its function(s) is not clarified. Even though the lost expression of DCC occurred in later stages of multistep colorectal carcinogenesis, its contribution to the onset or progression of ovarian cancer is not fully understood. To investigate DCC expression in ovarian cancer, we studied 254 clinical samples by RT-PCR. Our results revealed that 52% malignant ovarian cancer did not express DCC gene. By contrast, DCC expression was observed in all normal ovary tissues and 80% benign ovarian tumors. Obviously, there was a significant correlation between DCC expression and ovarian cancer, especially in the epithelial ovarian cancer. The present study also suggested that the loss expression of DCC occurred more frequently in the cases of later clinical stage, higher pathological grade, and poorer prognosis. In the other part of this study, we further explored DCC expression after transfection in two kinds of ovarian cancer cell lines, namely SKOV3 cell and HO-8910 cell, using RT-PCR and immunocytochemistry. The results indicated that DCC expressed in SKOV3-DCC and HO-8910-DCC cells, and ultrastructural analysis showed the appearance of apoptotic features in them. Furthermore, cell growth was markedly down-regulated in above groups of cells, indicating that transfection with the DCC constructs can suppress the growth of tumor cells. In conclusion, our results suggest an association of lost expression of DCC with the ovarian cancer, and DCC gene may inhibit the growth of ovarian carcinoma cells. However, this result needs further trials with a larger sample. PMID:20054719

  3. Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth.

    PubMed

    Yokoyama, Y; Dhanabal, M; Griffioen, A W; Sukhatme, V P; Ramakrishnan, S

    2000-04-15

    Ovarian cancer is the leading cause of fatality among gynecological malignancies. Ovarian cancer growth is angiogenesis-dependent, and an increased production of angiogenic growth factors such as vascular endothelial growth factor is prognostically significant even during early stages of the disease. Therefore, we investigated whether antiangiogenic treatment can be used to inhibit the growth of ovarian cancer in an experimental model system. Mouse angiostatin (kringle 1-4) and endostatin were expressed in yeast. Purified angiostatin and endostatin were then used to treat established ovarian cancers in athymic mice. These studies showed that both angiostatin and endostatin inhibited tumor growth. However, angiostatin treatment was more effective in inhibiting ovarian cancer growth when compared with endostatin in parallel experiments. Residual tumors obtained from angiostatin- and endostatin-treated animals showed decreased number of blood vessels and, as a consequence, increased apoptosis of tumor cells. Subsequently, the efficacy of a combined treatment with angiostatin and endostatin was investigated. In the presence of both angiostatic proteins, endothelial cell proliferation was synergistically inhibited. Similarly, a combination regimen using equal amounts of angiostatin and endostatin showed more than additive effect in tumor growth inhibition when compared with treatment with individual angiostatic protein. These studies demonstrate synergism between two angiostatic molecules and that antiangiogenic therapy can be used to inhibit ovarian cancer growth. PMID:10786683

  4. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    SciTech Connect

    Hashimoto, Kae; Morishige, Ken-ichirou . E-mail: mken@gyne.med.osaka-u.ac.jp; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  5. IKK inhibition increases bortezomib effectiveness in ovarian cancer

    PubMed Central

    Singha, Bipradeb; Gatla, Himavanth Reddy; Phyo, Sai; Patel, Atish; Chen, Zhe-Sheng; Vancurova, Ivana

    2015-01-01

    Ovarian cancer is associated with increased expression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which induces tumor cell proliferation, angiogenesis, and metastasis. Even though bortezomib (BZ) has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in ovarian cancer; however, the mechanisms are not understood. We have recently shown that BZ unexpectedly induces the expression of IL-8 in ovarian cancer cells in vitro, by IκB kinase (IKK)-dependent mechanism. Here, we tested the hypothesis that IKK inhibition reduces the IL-8 production and increases BZ effectiveness in reducing ovarian tumor growth in vivo. Our results demonstrate that the combination of BZ and the IKK inhibitor Bay 117085 significantly reduces the growth of ovarian tumor xenografts in nude mice when compared to either drug alone. Mice treated with the BZ/Bay 117085 combination exhibit smallest tumors, and lowest levels of IL-8. Furthermore, the reduced tumor growth in the combination group is associated with decreased tumor levels of S536P-p65 NFκB and its decreased recruitment to IL-8 promoter in tumor tissues. These data provide the first in vivo evidence that combining BZ with IKK inhibitor is effective, and suggest that using IKK inhibitors may increase BZ effectiveness in ovarian cancer treatment. PMID:26267322

  6. Ovarian Cancer

    MedlinePlus

    Ovarian Cancer There are five main types of cancer that affect a woman’s reproductive organs: cervical, ovarian, uterine, ... rare fallopian tube cancer.) This fact sheet about ovarian cancer is part of the Centers for Disease Control ...

  7. Ovarian Cancer

    MedlinePlus

    ... deaths than other female reproductive cancers. The sooner ovarian cancer is found and treated, the better your chance for recovery. But ovarian cancer is hard to detect early. Women with ovarian ...

  8. Ovarian cancer

    MedlinePlus

    Cancer - ovaries ... Ovarian cancer is the fifth most common cancer among women. It causes more deaths than any other type of female reproductive organ cancer. The cause of ovarian cancer is unknown. Risk ...

  9. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer

    PubMed Central

    Reusser, Nicole M; Dalton, Heather J; Pradeep, Sunila; Gonzalez-Villasana, Vianey; Jennings, Nicholas B; Vasquez, Hernan G; Wen, Yunfei; Rupaimoole, Rajesh; Nagaraja, Archana S; Gharpure, Kshipra; Miyake, Takahito; Huang, Jie; Hu, Wei; Lopez-Berestein, Gabriel; Sood, Anil K

    2014-01-01

    Purpose Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations. Experimental Design Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis. Results Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density. Conclusions Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer. PMID:24841852

  10. Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug☆

    PubMed Central

    Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

    2015-01-01

    Objective Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. Methods The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Results Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Conclusions Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. PMID:25172764

  11. Knockdown of EHF inhibited the proliferation, invasion and tumorigenesis of ovarian cancer cells.

    PubMed

    Cheng, Zhongping; Guo, Jing; Chen, Li; Luo, Ning; Yang, Weihong; Qu, Xiaoyan

    2016-06-01

    Ovarian cancer is the most lethal gynecologic malignancy worldwide. ETS homologous factor (EHF), a member of E26 transformation specific (ETS) transcription factors, has been reported overexpressed in ovarian cancer. However, the molecular mechanism underlying the biological function of EHF in ovarian cancer is still unclear. Here, we found that EHF was elevated in ovarian cancer tissues compared with non-tumorous tissues. Moreover, high EHF expression level was correlated with short survival time of patients with ovarian cancer. Knockdown of EHF in ovarian cancer cells, SKOV3 and OVCAR3, significantly inhibited cell proliferation and increased cells population in G1 phase. The proteins promoting cell cycles (Cyclin B1, Cyclin D1, and PCNA) were down-regulated and the protein negatively regulating cell cycle progression (P21) was up-regulated after EHF knockdown. Moreover, inhibition of EHF in ovarian cancer cells dramatically induced cell apoptosis, but impaired cell adhesion and cell invasion. Furthermore, phosphorylation levels of ERK and AKT were notably reduced in EHF knockdown cells. Finally, in vivo data showed that knockdown of EHF inhibited tumor growth in nude mice. Our data indicates that EHF could be a potential prognosis marker for ovarian cancer and work as an oncogene by targeting ERK and AKT signaling, which can serve as a new target for ovarian cancer treatment. © 2015 Wiley Periodicals, Inc. PMID:26258986

  12. Ovarian cancer

    MedlinePlus

    ... of ovarian cancer Already been diagnosed with ovarian cancer to determine how well treatment is working Other tests that may be done include: Complete blood count and blood chemistry Pregnancy test (serum HCG) CT or MRI of ...

  13. Gedunin, a novel natural substance, inhibits ovarian cancer cell proliferation.

    PubMed

    Kamath, Siddharth G; Chen, Ning; Xiong, Yin; Wenham, Robert; Apte, Sachin; Humphrey, Marcia; Cragun, Janiel; Lancaster, Johnathan M

    2009-12-01

    The discovery of more active therapeutic compounds is essential if the outcome for patients with advanced-stage epithelial ovarian cancer is to be improved. Gedunin, an extract of the neem tree, has been used as a natural remedy for centuries in Asia. Recently, gedunin has been shown to have potential in vitro antineoplastic properties; however, its effect on ovarian cancer cells is unknown. We evaluated the in vitro effect of gedunin on SKOV3, OVCAR4, and OVCAR8 ovarian cancer cell lines proliferation, alone and in the presence of cisplatin. Furthermore, we analyzed in vitro gedunin sensitivity data, integrated with genome-wide expression data from 54 cancer cell lines in an effort to identify genes and molecular pathways that underlie the mechanism of gedunin action. In vitro treatment of ovarian cancer cell lines with gedunin alone produced up to an 80% decrease in cell proliferation (P < 0.01) and, combining gedunin with cisplatin, demonstrated up to a 47% (P < 0.01) decrease in cell proliferation compared with cisplatin treatment alone. Bioinformatic analysis of integrated gedunin sensitivity and gene expression data identified 52 genes to be associated with gedunin sensitivity. These genes are involved in molecular functions related to cell cycle control, carcinogenesis, lipid metabolism, and molecular transportation. We conclude that gedunin has in vitro activity against ovarian cancer cells and, further, may enhance the antiproliferative effect of cisplatin. The molecular determinants of in vitro gedunin response are complex and may include modulation of cell survival and apoptosis pathways. PMID:19955938

  14. Ciglitazone enhances ovarian cancer cell death via inhibition of glucose transporter-1.

    PubMed

    Shin, So Jin; Kim, Jin Young; Kwon, Sun Young; Mun, Kyo-Cheol; Cho, Chi Heum; Ha, Eunyoung

    2014-11-15

    Ciglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist and improves insulin sensitivity. Apart from antidiabetic activity, ciglitazone elicits inhibitory effects on cancer cell growth. Recent studies indicate that glucose metabolism plays a key role in malignant diseases. Significant increase in glucose consumption is found under malignant conditions. The role of ciglitazone in cancer cell death in relation to glucose metabolism is unclear. Thus we designed this study to determine the effect of ciglitazone on glucose metabolism. First, we found ciglitazone inhibited glucose uptake in ovarian cancer cells but did not affect hexokinase activity. Ciglitazone decreased expression levels of glucose transporter-1 (GLUT-1). We also found that ciglitazone and siGLUT-1 treatments induced cell death in ovarian cancer cells. We identified that ciglitazone decreased expressions of specific protein 1 (Sp-1) and β-catenin while increased phosphorylation levels of AMP-activated protein kinase. In vivo study using NOD-scid IL2Rgamma(null) mice confirmed that ciglitazone significantly decreased ovarian cancer mass transplanted onto the back of the mice. Finally, we determined GLUT-1 expressions in patients with serous type ovarian cancer and found that GLUT-1 expression was markedly increased in cancer patients and expression level was proportional to the degree of cancer stages. These results suggest that ciglitazone induces apoptosis in ovarian cancer cells by the inhibition of GLUT-1 and provides a possible therapeutic effect of ciglitazone as an adjuvant drug in the treatment of ovarian cancer. PMID:25240713

  15. The angiogenesis regulator vasohibin-1 inhibits ovarian cancer growth and peritoneal dissemination and prolongs host survival.

    PubMed

    Takahashi, Yoshifumi; Saga, Yasushi; Koyanagi, Takahiro; Takei, Yuji; Machida, Sizuo; Taneichi, Akiyo; Mizukami, Hiroaki; Sato, Yasufumi; Matsubara, Shigeki; Fujiwara, Hiroyuki

    2015-12-01

    Vasohibin-1 (VASH1) is expressed in vascular endothelial cells stimulated by several angiogenic growth factors and displays autocrine activity to regulate angiogenesis via a negative feedback mechanism. In this study, we investigated the effect of VASH1 on ovarian cancer progression using VASH1-expressing ovarian cancer cells in vitro and in vivo. The growth ability of ovarian cancer cells engineered to express the VASH1 gene remained unchanged in vitro. However, we showed that VASH1 secretion by tumor cells inhibited the growth of human umbilical vein endothelial cells. Further, animal experiments showed that VASH1 expression inhibited tumor angiogenesis and growth. In a murine model of peritoneal dissemination of ovarian cancer cells, VASH1 inhibited peritoneal dissemination and ascites, resulting in significantly prolonged survival in mice. This indicates that VASH1 exerts an antitumor effect on ovarian cancer by inhibiting angiogenesis in the tumor environment. These findings suggest that a novel therapy based on VASH1 could be a useful therapeutic strategy for ovarian cancer. PMID:26460696

  16. The angiogenesis regulator vasohibin-1 inhibits ovarian cancer growth and peritoneal dissemination and prolongs host survival

    PubMed Central

    TAKAHASHI, YOSHIFUMI; SAGA, YASUSHI; KOYANAGI, TAKAHIRO; TAKEI, YUJI; MACHIDA, SIZUO; TANEICHI, AKIYO; MIZUKAMI, HIROAKI; SATO, YASUFUMI; MATSUBARA, SHIGEKI; FUJIWARA, HIROYUKI

    2015-01-01

    Vasohibin-1 (VASH1) is expressed in vascular endothelial cells stimulated by several angiogenic growth factors and displays autocrine activity to regulate angiogenesis via a negative feedback mechanism. In this study, we investigated the effect of VASH1 on ovarian cancer progression using VASH1-expressing ovarian cancer cells in vitro and in vivo. The growth ability of ovarian cancer cells engineered to express the VASH1 gene remained unchanged in vitro. However, we showed that VASH1 secretion by tumor cells inhibited the growth of human umbilical vein endothelial cells. Further, animal experiments showed that VASH1 expression inhibited tumor angiogenesis and growth. In a murine model of peritoneal dissemination of ovarian cancer cells, VASH1 inhibited peritoneal dissemination and ascites, resulting in significantly prolonged survival in mice. This indicates that VASH1 exerts an antitumor effect on ovarian cancer by inhibiting angiogenesis in the tumor environment. These findings suggest that a novel therapy based on VASH1 could be a useful therapeutic strategy for ovarian cancer. PMID:26460696

  17. PPARγ inhibits ovarian cancer cells proliferation through upregulation of miR-125b.

    PubMed

    Luo, Shuang; Wang, Jidong; Ma, Ying; Yao, Zhenwei; Pan, Hongjuan

    2015-06-26

    miR-125b has essential roles in coordinating tumor proliferation, angiogenesis, invasiveness, metastasis and chemotherapy recurrence. In ovarian cancer miR-125b has been shown to be downregulated and acts as a tumor suppressor by targeting proto-oncogene BCL3. PPARγ, a multiple functional transcription factor, has been reported to have anti-tumor effects through inhibition of proliferation and induction of differentiation and apoptosis by targeting the tumor related genes. However, it is unclear whether miR-125b is regulated by PPARγ in ovarian cancer. In this study, we demonstrated that the miR-125b downregulated in ovarian cancer tissues and cell lines. Ligands-activated PPARγ suppressed proliferation of ovarian cancer cells and this PPARγ-induced growth inhibition is mediated by the upregulation of miR-125b. PPARγ promoted the expression of miR-125b by directly binding to the responsive element in miR-125b gene promoter region. Thus, our results suggest that PPARγ can induce growth suppression of ovarian cancer by upregulating miR-125b which inhibition of proto-oncogene BCL3. These findings will extend our understanding of the function of PPARγ in tumorigenesis and miR-125b may be a therapeutic intervention of ovarian cancer. PMID:25944662

  18. PPARγ inhibits ovarian cancer cells proliferation through upregulation of miR-125b

    SciTech Connect

    Luo, Shuang; Wang, Jidong; Ma, Ying; Yao, Zhenwei; Pan, Hongjuan

    2015-06-26

    miR-125b has essential roles in coordinating tumor proliferation, angiogenesis, invasiveness, metastasis and chemotherapy recurrence. In ovarian cancer miR-125b has been shown to be downregulated and acts as a tumor suppressor by targeting proto-oncogene BCL3. PPARγ, a multiple functional transcription factor, has been reported to have anti-tumor effects through inhibition of proliferation and induction of differentiation and apoptosis by targeting the tumor related genes. However, it is unclear whether miR-125b is regulated by PPARγ in ovarian cancer. In this study, we demonstrated that the miR-125b downregulated in ovarian cancer tissues and cell lines. Ligands-activated PPARγ suppressed proliferation of ovarian cancer cells and this PPARγ-induced growth inhibition is mediated by the upregulation of miR-125b. PPARγ promoted the expression of miR-125b by directly binding to the responsive element in miR-125b gene promoter region. Thus, our results suggest that PPARγ can induce growth suppression of ovarian cancer by upregulating miR-125b which inhibition of proto-oncogene BCL3. These findings will extend our understanding of the function of PPARγ in tumorigenesis and miR-125b may be a therapeutic intervention of ovarian cancer. - Highlights: • miR-125b is down-regulated in ovarian cancer tissues and cells. • PPARγ upregulates miR-125b and downregulates its target gene BCL3 expression. • Silence of miR-125b attenuates PPARγ-mediated growth suppression of ovarian cancer cells. • PPARγ promotes the transcription of miR-125b via binding to PPARE in miR-125b gene promoter region.

  19. OVARIAN CANCER

    PubMed Central

    Cho, Kathleen R.; Shih, Ie-Ming

    2009-01-01

    Ovarian carcinomas are a heterogeneous group of neoplasms traditionally sub-classified based on type and degree of differentiation. Although current clinical management of ovarian carcinoma largely fails to take this heterogeneity into account, it is becoming evident that each major histological type has characteristic genetic defects that deregulate specific signaling pathways in the tumor cells. Moreover, within the most common histological types, the molecular pathogenesis of low-grade versus high-grade tumors appears to be largely distinct. Mouse models of ovarian carcinoma have been developed that recapitulate many of the morphological features, biological behavior, and gene expression patterns of selected subtypes of ovarian cancer. Such models will likely prove useful for studying ovarian cancer biology and for pre-clinical testing of molecularly targeted therapeutics, which may ultimately lead to better clinical outcomes for women with ovarian cancer. PMID:18842102

  20. The marine-derived fungal metabolite, terrein, inhibits cell proliferation and induces cell cycle arrest in human ovarian cancer cells.

    PubMed

    Chen, Yi-Fei; Wang, Shu-Ying; Shen, Hong; Yao, Xiao-Fen; Zhang, Feng-Li; Lai, Dongmei

    2014-12-01

    The difficulties faced in the effective treatment of ovarian cancer are multifactorial, but are mainly associated with relapse and drug resistance. Cancer stem-like cells have been reported to be an important contributor to these hindering factors. In this study, we aimed to investigate the anticancer activities of a bioactive fungal metabolite, namely terrein, against the human epithelial ovarian cancer cell line, SKOV3, primary human ovarian cancer cells and ovarian cancer stem-like cells. Terrein was separated and purified from the fermentation metabolites of the marine sponge-derived fungus, Aspergillus terreus strain PF26. Its anticancer activities against ovarian cancer cells were investigated by cell proliferation assay, cell migration assay, cell apoptosis and cell cycle assays. The ovarian cancer stem-like cells were enriched and cultured in a serum-free in vitro suspension system. Terrein inhibited the proliferation of the ovarian cancer cells by inducing G2/M phase cell cycle arrest. The underlying mechanisms involved the suppression of the expression of LIN28, an important marker gene of stemness in ovarian cancer stem cells. Of note, our study also demonstrated the ability of terrein to inhibit the proliferation of ovarian cancer stem-like cells, in which the expression of LIN28 was also downregulated. Our findings reveal that terrein (produced by fermention) may prove to be a promising drug candidate for the treatment of ovarian cancer by inhibiting the proliferation of cancer stem-like cells. PMID:25318762

  1. MiR181c inhibits ovarian cancer metastasis and progression by targeting PRKCD expression

    PubMed Central

    Yao, Lijuan; Wang, Li; Li, Fengxia; Gao, Xihai; Wei, Xuegong; Liu, Zhihui

    2015-01-01

    MicroRNAs (miRNAs) regulate many important cancer related gene expression in the posttranscriptional process. Dysregulated expression of miRNAs has been observed in numerous human cancers including ovarian cancer. In this study, we found that the expression of the miR-181c was significantly decreased in ovarian cancer tissue and in tissues with lymph node metastasis when compared with their control samples, respectively. Moreover, among pathological stages, the expression of miR-181c was significantly decreased in the tissues with IV stage compared with other stages. In vitro, miR-181c significantly inhibited the proliferation, metastasis of A2780 cell line, and induced G1 phase arrest. Through bioinformatics prediction, protein kinase C delta (PRKCD) was identified as a target gene of miR-181c. Western blot results showed that PRKCD was increased in ovarian cancer tissue, in tissues with lymph node metastasis and IV stage of ovarian cancer pathological samples. After knocking down PRKCD, the cell cycle of A2780 cells was also arrested in G1 phase. The proliferation and the metastasis of A2780 cells were reduced. The dual luciferase reporter experiments showed that miR-181c regulated the expression of PRKCD by combining with its 3’UTR. These results indicate that miR-181c inhibits ovarian cancer metastasis and progression by targeting PRKCD expression. PMID:26629004

  2. Dual HER/VEGF receptor targeting inhibits in vivo ovarian cancer tumor growth.

    PubMed

    Becker, Marc A; Farzan, Thahir; Harrington, Sean C; Krempski, James W; Weroha, S John; Hou, Xiaonan; Kalli, Kimberly R; Wong, Tai W; Haluska, Paul

    2013-12-01

    Ovarian cancer mortality ranks highest among all gynecologic cancers with growth factor pathways playing an integral role in tumorigenesis, metastatic dissemination, and therapeutic resistance. The HER and VEGF receptor (VEGFR) are both overexpressed and/or aberrantly activated in subsets of ovarian tumors. While agents targeting either the HER or VEGF pathways alone have been investigated, the impact of these agents have not led to overall survival benefit in ovarian cancer. We tested the hypothesis that cotargeting HER and VEGFR would maximize antitumor efficacy at tolerable doses. To this end, ovarian cancer xenografts grown intraperitoneally in athymic nude mice were tested in response to AC480 (pan-HER inhibitor, "HERi"), cediranib (pan-VEGFR inhibitor "VEGFRi"), or BMS-690514 (combined HER/VEGFR inhibitor "EVRi"). EVRi was superior to both HERi and VEGFRi in terms of tumor growth, final tumor weight, and progression-free survival. Correlative tumor studies employing phosphoproteomic antibody arrays revealed distinct agent-specific alterations, with EVRi inducing the greatest overall effect on growth factor signaling. These data suggest that simultaneous inhibition of HER and VEGFR may benefit select subsets of ovarian cancer tumors. To this end, we derived a novel HER/VEGF signature that correlated with poor overall survival in high-grade, late stage, serous ovarian cancer patient tumors. PMID:24130056

  3. Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene

    PubMed Central

    Luo, Li; Du, Ting; Zhang, Jiumeng; Zhao, Wei; Cheng, Hao; Yang, Yuping; Wu, Yujiao; Wang, Chunmei; Men, Ke; Gou, Maling

    2016-01-01

    Gene therapy has promising applications in ovarian cancer therapy. Blocking the function of the survivin protein could lead to the growth inhibition of cancer cells. Herein, we used degradable heparin–polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human survivin T34A (hs-T34A) gene to treat ovarian cancer. HPEI nanoparticles were characterized and were found to have a dynamic diameter of 66±4.5 nm and a zeta potential of 27.1±1.87 mV. The constructed hs-T34A gene expression plasmid could be effectively delivered into SKOV3 ovarian carcinoma cells by HPEI nanoparticles with low cytotoxicity. Intraperitoneal administration of HPEI/hs-T34A complexes could markedly inhibit tumor growth in a mouse xenograft model of SKOV3 human ovarian cancer. Moreover, according to our results, apparent apoptosis of cancer cells was observed both in vitro and in vivo. Taken together, the prepared HPEI/hs-T34A formulation showed potential applications in ovarian cancer gene therapy. PMID:26893558

  4. Inhibition of HDAC1 and DNMT1 Modulate RGS10 Expression and Decrease Ovarian Cancer Chemoresistance

    PubMed Central

    Cacan, Ercan; Ali, Mourad W.; Boyd, Nathaniel H.; Hooks, Shelley B.; Greer, Susanna F.

    2014-01-01

    RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance. PMID:24475290

  5. The Wedelolactone Derivative Inhibits Estrogen Receptor-Mediated Breast, Endometrial, and Ovarian Cancer Cells Growth

    PubMed Central

    Xu, Defeng; Lin, Tzu-Hua; Cheng, Max A.; Chen, Lu-Min; Chang, Chawnshang; Yeh, Shuyuan

    2014-01-01

    Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers. PMID:25221777

  6. Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene.

    PubMed

    Luo, Li; Du, Ting; Zhang, Jiumeng; Zhao, Wei; Cheng, Hao; Yang, Yuping; Wu, Yujiao; Wang, Chunmei; Men, Ke; Gou, Maling

    2016-01-01

    Gene therapy has promising applications in ovarian cancer therapy. Blocking the function of the survivin protein could lead to the growth inhibition of cancer cells. Herein, we used degradable heparin-polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human survivin T34A (hs-T34A) gene to treat ovarian cancer. HPEI nanoparticles were characterized and were found to have a dynamic diameter of 66±4.5 nm and a zeta potential of 27.1±1.87 mV. The constructed hs-T34A gene expression plasmid could be effectively delivered into SKOV3 ovarian carcinoma cells by HPEI nanoparticles with low cytotoxicity. Intraperitoneal administration of HPEI/hs-T34A complexes could markedly inhibit tumor growth in a mouse xenograft model of SKOV3 human ovarian cancer. Moreover, according to our results, apparent apoptosis of cancer cells was observed both in vitro and in vivo. Taken together, the prepared HPEI/hs-T34A formulation showed potential applications in ovarian cancer gene therapy. PMID:26893558

  7. Ovarian cancer.

    PubMed

    Matulonis, Ursula A; Sood, Anil K; Fallowfield, Lesley; Howitt, Brooke E; Sehouli, Jalid; Karlan, Beth Y

    2016-01-01

    Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. PMID:27558151

  8. T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin.

    PubMed

    Dziegielewska, Barbara; Casarez, Eli V; Yang, Wesley Z; Gray, Lloyd S; Dziegielewski, Jaroslaw; Slack-Davis, Jill K

    2016-03-01

    Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type calcium (Ca(2+)) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca(2+) channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca(2+) channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the antiapoptotic gene survivin (BIRC5). Analysis of intracellular signaling revealed mibefradil reduced AKT phosphorylation, increased the levels and nuclear retention of FOXO transcription factors that repress BIRC5 expression, and decreased the expression of FOXM1, which promotes BIRC5 expression. Combining carboplatin with mibefradil synergistically increased apoptosis in vitro. Importantly, mibefradil rendered platinum-resistant ovarian tumors sensitive to carboplatin in a mouse model of peritoneal metastasis. Together, the data provide rationale for future use of T-type channel antagonists together with platinum agents for the treatment of ovarian cancer. Mol Cancer Ther; 15(3); 460-70. ©2016 AACR. PMID:26832797

  9. miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2

    PubMed Central

    ZHAO, XIAOJUAN; ZHOU, YUN; CHEN, YU; YU, FENG

    2016-01-01

    MicroRNAs (miRs) have been reported to be key regulators in numerous types of cancer. The aim of the present study was to investigate the role of miR-494 in ovarian cancer. Expression of miR-494 was analyzed in ovarian cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-494 mimic or negative control was transiently transfected into A2780 and SKOV3 cell lines. A cell counting kit-8 assay was performed to assess the effects of miR-494 on cell proliferation, and flow cytometry was used to evaluate the apoptotic rate. The target gene of miR-494 was detected by luciferase assay. Expression of fibroblast growth factor receptor 2 (FGFR2) was identified using RT-qPCR and western blotting. In the present study, decreased expression of miR-494 was observed in ovarian cancer samples and cell lines. Overexpression of miR-494 inhibited ovarian cancer cell proliferation by inducing apoptosis. Additional investigation indicated that FGFR2 was a direct target of miR-494. Taken together, the results of the present study suggested that miR-494 suppressed ovarian cancer cell proliferation by inducing apoptosis via targeting FGFR2. PMID:27313773

  10. Ovarian Cancer FAQ

    MedlinePlus

    ... Ovarian Cancer Patient Education FAQs Ovarian Cancer Patient Education Pamphlets - Spanish Ovarian Cancer FAQ096, April 2015 PDF Format Ovarian ... Your Practice Patient Safety & Quality Payment Reform (MACRA) Education & Events Annual ... Pamphlets Teen Health About ACOG About Us Leadership & ...

  11. Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

    PubMed

    Prudnikova, T Y; Villamar-Cruz, O; Rawat, S J; Cai, K Q; Chernoff, J

    2016-04-28

    p21-activated kinases (Paks) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1-amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13-amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21(Cip) and decreased expression of cyclin B1. These findings suggest that small-molecule inhibitors of Pak1 may have a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification. PMID:26257058

  12. What Is Ovarian Cancer?

    MedlinePlus

    ... the key statistics about ovarian cancer? What is ovarian cancer? Cancer starts when cells in the body begin ... section . Other cancers that are similar to epithelial ovarian cancer Primary peritoneal carcinoma Primary peritoneal carcinoma (PPC) is ...

  13. Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer.

    PubMed

    Henry, C E; Llamosas, E; Djordjevic, A; Hacker, N F; Ford, C E

    2016-01-01

    Ovarian cancer survival remains poor despite recent advances in our understanding of genetic profiles. Unfortunately, the majority of ovarian cancer patients have recurrent disease after chemotherapy and lack other treatment options. Wnt signalling has been extensively implicated in cancer progression and chemoresistance. Therefore, we investigated the previously described Wnt receptors ROR1 and ROR2 as regulators of epithelial-to-mesenchymal transition (EMT) in a clinically relevant cell line model. The parental A2780- and cisplatin-resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Proliferation, adhesion, migration and invasion were measured after transient overexpression of ROR1 and ROR2 in the parental A2780 cell line, and silencing of ROR1 and ROR2 in the A2780-cis cell line. Here we show that ROR1 and ROR2 expression is increased in A2780-cis cells, alongside β-catenin-independent Wnt targets. Knockdown of ROR1 and ROR2 significantly inhibited cell migration and invasion and simultaneous knockdown of ROR1 and ROR2 significantly sensitised cells to cisplatin, whilereas ROR overexpression in the parental cell line increased cell invasion. Therefore, ROR1 and ROR2 have the potential as novel drug targets in metastatic and recurrent ovarian cancer patients. PMID:27239958

  14. CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer.

    PubMed

    Higuchi, Tomoe; Flies, Dallas B; Marjon, Nicole A; Mantia-Smaldone, Gina; Ronner, Lukas; Gimotty, Phyllis A; Adams, Sarah F

    2015-11-01

    Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. PMID:26138335

  15. Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells.

    PubMed

    Seo, Jeong-Ah; Kim, Boyun; Dhanasekaran, Danny N; Tsang, Benjamin K; Song, Yong Sang

    2016-02-01

    Aberrant increase in the expression levels of sarco/endoplasmic reticulum calcium ATPase (SERCA), which regulates Ca(2+) homeostasis, has been observed in ovarian cancers. In this study, we demonstrated that curcumin increases cytosolic Ca(2+) concentration through inhibition of SERCA activity, causing apoptosis in ovarian cancer cells but not in normal cells, including peripheral blood mononuclear cells (PBMCs) and ovarian surface epithelial cells (OSE). Curcumin induced apoptosis in ovarian cancer cells in a concentration- and time-dependent manner. Cytosolic Ca(2+) flux was evident after the curcumin treatment (15 µM). Treatment with Ca(2+) chelator reduced curcumin-induced apoptosis, confirming the possible involvement of increased cytosolic Ca(2+) concentration in this response. Basal mRNA and protein levels of SERCA2 were significantly higher in ovarian cancer cells than in OSE. SERCA activity was suppressed by curcumin, with no effect on protein expression. Forced expression of the SERCA2b gene in ovarian cancer cells prevented curcumin-induced cytosolic Ca(2+) elevation and subsequent apoptosis, supporting an important role of SERCA in curcumin-induced apoptosis of ovarian cancer cells. Taken together, inhibition of SERCA activity by curcumin disrupts the Ca(2+) homeostasis and thereby promotes apoptosis in ovarian cancer cells. PMID:26607901

  16. Sohlh2 inhibits human ovarian cancer cell invasion and metastasis by transcriptional inactivation of MMP9.

    PubMed

    Zhang, Haiyu; Hao, Chunyan; Wang, Yang; Ji, Shufang; Zhang, Xiaoli; Zhang, Wenfang; Zhao, Qinghao; Sun, Jinhao; Hao, Jing

    2016-07-01

    Identifying key mediators of cancer invasion and metastasis is crucial to the development of new and more effective therapies. We previously identified Sohlh2 as an important inhibitor of ovarian cancer cell proliferation. However, the function of Sohlh2 in cell migration and invasion remains unknown. In this paper, we report a novel Sohlh2 to MMP9 signaling pathway in the invasive ovarian cancer. Using immunohistochemistry staining, we revealed Sohlh2 expression was inversely correlated with the invasive human ovarian cancers. In vitro experiments, forced expression of Sohlh2 led to a significant reduction in cancer cell migration and invasion. Conversely, silencing of Sohlh2 enhanced ovarian cancer cell migration and invasion. Experiments using nude mice demonstrated that the ectopic Sohlh2 expression inhibited the HO8910 cell capability of the metastasis to the lungs and livers. Ectopic overexpression of Sohlh2 in the invasive HO8910 cells reduced the MMP9 expression, whereas Sohlh2 knockdown from the non-invasive, SKOV3 cells increased the MMP9 expression. Promoter activation and binding analyses indicated that Sohlh2 repressed the MMP9 expression by directly acting on the MMP9 gene promoter. Inhibition of MMP9 dramatically blocked the Sohlh2 knockdown-enhanced SKOV3 cell invasion, and ectopic expression of MMP9 compensated for the anti-invasive activity of Sohlh2 in HO8910 cells. Overall, these results demonstrate for the first time that Sohlh2 functions as a tumor metastasis suppressor. Modulation of Sohlh2 expression has the potential to be a target for cancer therapy. © 2015 Wiley Periodicals, Inc. PMID:26153894

  17. Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells.

    PubMed

    Luo, Haitao; Rankin, Gary O; Liu, Lingzhi; Daddysman, Matthew K; Jiang, Bing-Hua; Chen, Yi Charlie

    2009-01-01

    Ovarian cancer is 1 of the most significant malignancies in the Western world, and the antiangiogenesis strategy has been postulated for prevention and treatment of ovarian cancers. Kaempferol is a natural flavonoid present in many fruits and vegetables. The antiangiogenesis potential of kaempferol and its underlying mechanisms were investigated in two ovarian cancer cell lines, OVCAR-3 and A2780/CP70. Kaempferol mildly inhibits cell viability but significantly reduces VEGF gene expression at mRNA and protein levels in both ovarian cancer cell lines. In chorioallantoic membranes of chicken embryos, kaempferol significantly inhibits OVCAR-3-induced angiogenesis and tumor growth. HIF-1alpha, a regulator of VEGF, is downregulated by kaempferol treatment in both ovarian cancer cell lines. Kaempferol also represses AKT phosphorylation dose dependently at 5 to 20 muM concentrations. ESRRA is a HIF-independent VEGF regulator, and it is also downregulated by kaempferol in a dose-dependent manner. Overall, this study demonstrated that kaempferol is low in cytotoxicity but inhibits angiogenesis and VEGF expression in human ovarian cancer cells through both HIF-dependent (Akt/HIF) and HIF-independent (ESRRA) pathways and deserves further studies for possible application in angio prevention and treatment of ovarian cancers. PMID:19838928

  18. Targeting the ROR1 and ROR2 receptors in epithelial ovarian cancer inhibits cell migration and invasion

    PubMed Central

    Henry, Claire; Llamosas, Estelle; Knipprath-Mészáros, Alexandra; Schoetzau, Andreas; Obermann, Ellen; Fuenfschilling, Maya; Caduff, Rosemarie; Fink, Daniel; Hacker, Neville; Ward, Robyn; Heinzelmann-Schwarz, Viola; Ford, Caroline

    2015-01-01

    AIM In recent years, the Wnt signalling pathway has been implicated in epithelial ovarian cancer and its members have potential as diagnostic, prognostic and therapeutic targets. Here we investigated the role of two Wnt receptor tyrosine kinases (RTKs), ROR1 and ROR2, and their putative ligand, Wnt5a, in ovarian cancer. METHODS Immunohistochemistry for ROR2 was performed in a large patient cohort, including benign controls, borderline tumours and epithelial ovarian cancer. In addition, siRNA was used to silence ROR1, ROR2 and Wnt5a individually, and together, in two ovarian cancer cell lines, and the effects on cell proliferation, adhesion, migration and invasion were measured. RESULTS ROR2 expression is significantly increased in ovarian cancer patients compared to patients with benign disease. In vitro assays showed that silencing either receptor inhibits ovarian cancer cell migration and invasion, and concurrently silencing both receptors has an even stronger inhibitory effect on proliferation, migration and invasion. CONCLUSIONS ROR2 expression is increased in epithelial ovarian cancer, and silencing ROR2 and its sister receptor ROR1 has a strong inhibitory effect on the ability of ovarian cancer cells to proliferate, migrate and invade through an extracellular matrix. PMID:26515598

  19. Bisdemethoxycurcumin inhibits ovarian cancer via reducing oxidative stress mediated MMPs expressions

    PubMed Central

    Pei, Haifeng; Yang, Yi; Cui, Lin; Yang, Jiong; Li, Xiuchuan; Yang, Yongjian; Duan, Haixia

    2016-01-01

    As one main active compound of curcuminoids, Bisdemethoxycurcumin (BDMC) possesses several biological activities, such as anti-inflammation and anti-cancer activities. However, the detailed mechanism of BDMC’s anti-metastasis activity in ovarian cancer has not been clearly elucidated yet. In the present study, cell proliferation, wound healing motility, cell adhesion and invasion with or without BDMC were determined. In addition, western blot was used to examine proteins expressions. The lucigenin-enhanced luminescence was introduced to assess cellular oxidative stress. The luciferase reporter gene assay was introduced to evaluate the transcriptional activity of NF-κB. Finally, BDMC significantly inhibited the adhesion, migration, invasion and metastasis of SKOV-3 cells. Moreover, BDMC inhibited expressions of several degradation-associated proteins, such as matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), CD147, urokinase plasminogen activator (uPA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), whereas increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), in a dose-dependent manner. In addition, BDMC reduced generation of cellular superoxide in a dose-dependent manner. Furthermore, BDMC inhibited the phosphorylation levels of NF-κB p65 and IκB-α, and consequently reduced NF-κB-driven luciferase expression. Collectively, BDMC serves as a therapeutic medicine to suppress ovarian cancer, perhaps via inhibiting cellular oxidative stress and subsequently inactivating NF-κB pathway. PMID:27349797

  20. A Mixed Methods Feasibility Trial of PKCι Inhibition with Auranofin in Asymptomatic Patients with Ovarian Cancer

    PubMed Central

    Jatoi, Aminah; Breitkopf, Carmen Radecki; Foster, Nathan R.; Block, Matthew S.; Grudem, Megan; Hendrickson, Andrea Wahner; Carlson, Rachel E.; Barrette, Brigitte; Karlin, Nina; Fields, Alan P.

    2015-01-01

    Purpose This trial was undertaken to 1) determine the feasibility of enrolling asymptomatic ovarian cancer patients with Ca-125 elevation to a trial with the PKCι inhibitor, auranofin, and 2) understand patients’ perceptions of Ca-125 monitoring. Methods Asymptomatic ovarian cancer patients with Ca-125 elevation received auranofin 3 mg orally twice/day and were evaluated. Patients participated in interviews about Ca-125 monitoring. Results Ten patients were enrolled in slightly over 6 months, exceeding our anticipated rate. Four manifested stable Ca-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% confidence interval: 1.3, 3.8 months); auranofin was well tolerated. One patient had baseline and monthly Ca-125 levels of 5570, 6085, 3511, and 2230 units/mL, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in Ca-125 to 7168 units/mL approximately 3 months later. Patient interviews revealed: 1) the important role of Ca-125 in cancer monitoring; 2) ardent advocacy for Ca-125 testing; and 3) evolution toward the Ca-125 assuming a life of its own. Conclusions This study showed feasibility; and patients favored Ca-125 monitoring. One patient had a decline in Ca-125, suggesting that PKCι inhibition merits further study in ovarian cancer. PMID:25502607

  1. Müllerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics

    PubMed Central

    Wei, Xiaolong; Dombkowski, David; Meirelles, Katia; Pieretti-Vanmarcke, Rafael; Szotek, Paul P.; Chang, Henry L.; Preffer, Frederic I.; Mueller, Peter R.; Teixeira, Jose; MacLaughlin, David T.; Donahoe, Patricia K.

    2010-01-01

    Cancer stem cells are proposed to be tumor-initiating cells capable of tumorigenesis, recurrence, metastasis, and drug resistance, and, like somatic stem cells, are thought to be capable of unlimited self-renewal and, when stimulated, proliferation and differentiation. Here we select cells by expression of a panel of markers to enrich for a population with stem cell-like characteristics. A panel of eight was initially selected from 95 human cell surface antigens as each was shared among human ovarian primary cancers, ovarian cancer cell lines, and normal fimbria. A total of 150 combinations of markers were reduced to a panel of three—CD44, CD24, and Epcam—which selected, in three ovarian cancer cell lines, those cells which best formed colonies. Cells expressing CD44, CD24, and Epcam exhibited stem cell characteristics of shorter tumor-free intervals in vivo after limiting dilution, and enhanced migration in invasion assays in vitro. Also, doxorubicin, cisplatin, and paclitaxel increased this enriched population which, conversely, was significantly inhibited by Müllerian inhibiting substance (MIS) or the MIS mimetic SP600125. These findings demonstrate that flow cytometry can be used to detect a population which shows differential drug sensitivity, and imply that treatment of patients can be individualized to target both stem/progenitor cell enriched and nonenriched subpopulations. The findings also suggest that this population, amenable to isolation by flow cytometry, can be used to screen for novel treatment paradigms, including biologic agents such as MIS, which will improve outcomes for patients with ovarian cancer. PMID:20952655

  2. Aspirin inhibits growth of ovarian cancer by upregulating caspase-3 and downregulating bcl-2

    PubMed Central

    LI, LIN; MAO, XIAOGANG; QIN, XIAOMIN; ZHOU, MIN; XING, HUI; DONG, FAN; JIANG, XIAOYUAN; ZHUANG, WENHUI

    2016-01-01

    The aim of the present study was to investigate the effect and mechanism of different concentrations of aspirin in inhibiting the ovarian cancer of p53N236S gene knock-in mice. In total, 28 male p53S mice, with an age range of 4–6 weeks and weight of 20–25 g were selected. The animals were transplanted with SKOV3 cells to establish subdermal human ovarian cancer. The mice were randomly divided into different groups according to the aspirin concentrations (mmol/l) used, i.e., 0, 1, 2 and 3. Subsequently, intraperitoneal injection was performed once every two days for 3 weeks. The tumor volume, lifetime, tumor cell proliferation inhibition rates, caspase-3 protein and bcl-2 protein expression of the four groups were analyzed and compared. Following aspirin treatment for 1, 2 and 3 weeks, the tumor volume of the 3 mmol/l aspirin group was significantly smaller than the other groups (P<0.05). The higher concentration of aspirin led to a smaller tumor size (P<0.05). The cell proliferation inhibition rate of the 3 mmol/l aspirin group was significantly larger than that of other groups (P<0.05). The relative expression level of caspase-3, bcl-2 protein of the 3 mmol/l aspirin group was significantly improved and reduced, respectively. In conclusion, aspirin can inhibit the growth of ovarian cancer of p53S rats due to its upregulation of the expression of caspase-3 protein and downregulation of the expression of bcl-2 protein. PMID:27347106

  3. The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life

    PubMed Central

    Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo

    2015-01-01

    Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life. PMID:26413541

  4. Symptoms of Ovarian Cancer

    MedlinePlus

    ... Informed Cancer Home What Are the Symptoms of Ovarian Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Gynecologic cancer symptoms diaries Ovarian cancer may cause one or more of these signs ...

  5. Ursolic acid inhibits the proliferation of human ovarian cancer stem-like cells through epithelial-mesenchymal transition.

    PubMed

    Zhang, Jie; Wang, Wenjing; Qian, Lin; Zhang, Qiuwan; Lai, Dongmei; Qi, Cong

    2015-11-01

    Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent. PMID:26323892

  6. Enhancement of triptolide-loaded micelles on tumorigenicity inhibition of human ovarian cancer.

    PubMed

    Wang, You; Liu, Ting; Li, He

    2016-05-01

    Triptolide (TP), a diterpenoid obtained from Tripterygium wilfordii Hook.f, has shown its antitumor activities against a variety of cancers in vitro in recent years. Unfortunately, TP has a small margin between the therapeutic and toxic doses and shows serious toxicity which limits its uses in antitumor treatment. In our previous study, Triptolide-loaded micelles (TP micelles), a TP drug delivery system with a sustained release behavior, had been reported to decrease TP uptake in the liver to relieve its toxicity, and increase TP distribution in the ovary to enhance its effects. This work therefore aimed at evaluating the inhibitory ability of TP micelles in the proliferation, apoptosis, invasion, and migration, and compared with free TP in SKOV3 cells. Our results showed that TP micelles inhibited the proliferation of SKOV3 in a time- and dose-dependent manner, and exhibited enhanced inhibition following 48 and 72 h treatment compared to TP. Cell cycle analysis revealed that TP and TP micelles inhibited cell proliferation by blocking their progression from the G2/M phase to the S phase. Although TP induced a significant increase in cell apoptosis, TP micelles showed a superior effect following 48 and 72 h treatment. Induction of caspase-dependent way and inhibition of NF-κB activation were found to be involved in the mechanism of TP micelles-induced apoptosis. Furthermore, the wound healing assay and transwell assay showed that both TP and TP micelles could obviously inhibit SKOV3 cells migration and invasion. Overall, TP micelles exhibited enhanced therapeutic efficacy in ovarian cancer in vitro due to its prolonged release and redistribution compared with the free TP. TP micelles might lead to an increase in tumorigenicity inhibition and a decrease in resistance and incidence simultaneously, indicating that it offers a new strategy with promising characteristics for TP chemotherapy application for ovarian cancer. PMID:26786618

  7. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    SciTech Connect

    Kim, Soyeon; Lee, Jae-Jung; Heo, Dae Seog

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands

  8. Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer

    PubMed Central

    Litchfield, Lacey M.; Mukherjee, Abir; Eckert, Mark A.; Johnson, Alyssa; Mills, Kathryn A.; Pan, Shawn; Shridhar, Viji; Lengyel, Ernst; Romero, Iris L.

    2015-01-01

    Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes. PMID:26172303

  9. Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

    PubMed Central

    Lei, Hu; Wei, Wei; Wang, Ying-Ying; Ma, Chun-Min; Gao, Feng-Hou; Xu, Han-Zhang; Wu, Ying-Li

    2015-01-01

    Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells. PMID:26134508

  10. Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells.

    PubMed

    Qin, Dong-Jun; Tang, Cai-Xia; Yang, Li; Lei, Hu; Wei, Wei; Wang, Ying-Ying; Ma, Chun-Min; Gao, Feng-Hou; Xu, Han-Zhang; Wu, Ying-Li

    2015-01-01

    Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells. PMID:26134508

  11. Ovarian Cancer Fact Sheet

    MedlinePlus

    ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Around one in every 60 ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Are some women more at ...

  12. VEGFR3 Inhibition Chemosensitizes Ovarian Cancer Stemlike Cells through Down-Regulation of BRCA1 and BRCA212

    PubMed Central

    Lim, Jaeyoung; Yang, Kun; Taylor-Harding, Barbie; Wiedemeyer, W. Ruprecht; Buckanovich, Ronald J.

    2014-01-01

    In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2. Inhibition of VEGFR3 in ovarian tumor cells was associated with growth arrest. CD133+ ovarian cancer stemlike cells were preferentially susceptible to VEGFR3-mediated growth inhibition. VEGFR3 inhibition–mediated down-regulation of BRCA gene expression reversed chemotherapy resistance and restored chemosensitivity in resistant cell lines in which a BRCA2 mutation had reverted to wild type. Finally, we demonstrate that tumor-associated macrophages are a primary source of VEGF-C in the tumor microenvironment. Our studies suggest that VEGFR3 inhibition may be a pharmacologic means to downregulate BRCA genes and improve the outcomes of patients with BRCA wild-type tumors. PMID:24862760

  13. Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy.

    PubMed

    Sun, Yang; Jin, Long; Liu, Jia-Hua; Sui, Yu-Xia; Han, Li-Li; Shen, Xiao-Li

    2016-09-01

    We aimed to determine the effects of the inhibition of enhancer of zeste homolog 2 (EZH2) gene expression on the cisplatin resistance of the human ovarian cancer cell line, SKOV3/DDP, and to identify the underlying mechanisms. SKOV3/DDP cells were stably transfected with pSUPER-EZH2 (EZH2 RNA interference plasmid) or pcDNA3.1-EZH2 (EZH2 gene overexpression plasmid) using the lipofection method. Real-time fluorescence quantitative reverse transcription polymerase chain reaction and western blotting confirmed that EZH2 expression was downregulated in pSUPER-EZH2-transfected cells. Flow cytometry revealed that EZH2 inhibition did not induce apoptosis, but significantly inhibited autophagy. In addition, it significantly increased the expression of the cellular senescence-signaling proteins p14(ARF), p16(INK4a), p53, pRb, and p21, and significantly decreased the expression of cyclin-dependent kinase (CDK)1, CDK2, and H3K27me3. Cellular senescence was characterized by a significant increase in the G0/G1 ratio and the restoration of sensitivity to cisplatin in the drug-resistant cells. These findings suggest that interfering with EZH2 expression can inhibit SKOV3/DDP cell autophagy and reverse resistance to cisplatin. The underlying mechanisms could be associated with the regulation of the cellular senescence-signaling pathway. PMID:27610467

  14. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.

    PubMed

    Sociali, Giovanna; Raffaghello, Lizzia; Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

    2016-01-19

    Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors. PMID:26658104

  15. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model

    PubMed Central

    Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

    2016-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5′-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors. PMID:26658104

  16. Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition

    PubMed Central

    Amatangelo, Michael D.; Garipov, Azat; Li, Hua; Conejo-Garcia, Jose R.; Speicher, David W.; Zhang, Rugang

    2013-01-01

    Inhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppress the growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations in EZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2. Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important to investigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the current study, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells that overexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOC cells with GSK343, a specific inhibitor of EZH2 methyltransferase, decreases the level of H3K27Me3, the product of EZH2’s enzymatic activity. However, GSK343 exhibited limited effects on the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343 significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix (ECM), which more closely mimics the tumor microenvironment in vivo. Notably, GSK343 induces apoptosis of EOC cells in 3D but not 2D culture. In addition, GSK343 significantly inhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cells to EZH2 methyltransferase inhibition, which suppresses cell growth, induces apoptosis and inhibits invasion. Our findings imply that in EZH2 wild-type solid tumors, the ECM tumor microenvironment plays an important role in determining sensitivity to EZH2 inhibition and suggest that targeting the ECM represents a novel strategy for enhancing EZH2 inhibitor efficacy. PMID:23759589

  17. Inhibition of integrin β1 decreases the malignancy of ovarian cancer cells and potentiates anticancer therapy via the FAK/STAT1 signaling pathway

    PubMed Central

    ZHANG, LEI; ZOU, WEN

    2015-01-01

    Integrin β1 (ITGB1) is frequently upregulated in ovarian cancer, and promotes ovarian tumorigenesis and cancer progression. However, the effects of ITGB1 inhibition on ovarian cancer progression and anticancer therapy remain to be elucidated. The results of the present study indicated that ITGB1 was upregulated in HO-8910 and HO-8910PM ovarian cancer cell lines, and knockdown of ITGB1 using short hairpin RNA markedly increased tumor cell apoptosis, decreased tumor cell adhesion and migration, and reduced tumor cell invasion by suppressing matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, the results of the present study provided evidence regarding the role of ITGB1 inhibition in bevacizumab anticancer therapy. The activation of signal transducer and activator of transcription 1 (STAT1) by focal adhesion kinase (FAK) is involved in integrin-mediated cell migration and adhesion. In the present study, the expression levels of FAK were markedly upregulated in ovarian cancer. The adherence and migratory potentials of ovarian cancer cells were significantly reduced when the FAK/STAT1 signaling pathway was inhibited by fludarabine. The results of the present study demonstrated that ITGB1 inhibition effectively reduced tumorigenesis and disease exacerbation, and contributed to bevacizumab anticancer therapy via the FAK/STAT1 signaling pathway, suggesting that inhibition of ITGB1 is a potential novel therapeutic strategy for ovarian carcinogenesis. PMID:26497667

  18. Claudin and ovarian cancer

    PubMed Central

    Bose, Chinmoy K.; Mukhopadhyay, Ashis

    2010-01-01

    Claudins are a family of proteins and the most important component of the tight junction. They constitute a paracellular barrier that controls the flow of molecules in the intercellular space of an epithelium. Although it seems that claudin should be down regulated in cancer cell, some claudins are, in fact highly elevated in various human cancers, including ovarian cancer. Whereas the functional significance of claudin overexpression in ovarian carcinoma is unclear, these proteins are important for migration, invasion, and survival of ovarian cancer cells. They clearly represent a general pathway in tumorigenesis, are a novel marker for ovarian cancer and may become a target for therapy or diagnosis of this disease. PMID:24591894

  19. Claudin and ovarian cancer.

    PubMed

    Bose, Chinmoy K; Mukhopadhyay, Ashis

    2010-01-01

    Claudins are a family of proteins and the most important component of the tight junction. They constitute a paracellular barrier that controls the flow of molecules in the intercellular space of an epithelium. Although it seems that claudin should be down regulated in cancer cell, some claudins are, in fact highly elevated in various human cancers, including ovarian cancer. Whereas the functional significance of claudin overexpression in ovarian carcinoma is unclear, these proteins are important for migration, invasion, and survival of ovarian cancer cells. They clearly represent a general pathway in tumorigenesis, are a novel marker for ovarian cancer and may become a target for therapy or diagnosis of this disease. PMID:24591894

  20. Combination of Fenretinide and Selenite Inhibits Proliferation and Induces Apoptosis in Ovarian Cancer Cells

    PubMed Central

    Liu, Jie; Li, Jia; Zhang, Jian-Fang; Xin, Xiao-Yan

    2013-01-01

    The combination of fenretinide and selenite on ovarian cancer cells was investigated to assess its effects on proliferation and ability to induce apoptosis. Our results showed that fenretinide and selenite in combination significantly suppress the proliferation of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation, and the loss of mitochondrial membrane potential) compared with either drug used alone. The caspase3/9-dependent pathway was triggered significantly in combination treatment, and moreover, the AMPK pathway also mediated the apoptosis induction in fenretinide and selenite combination. Fenretinide and selenite combination treatment was demonstrated to suppress tumor growth in vivo, this drug combination has been thus found to have an enhanced anti-tumor effect on ovarian cancers cells. PMID:24192821

  1. Nitidine chloride inhibits proliferation, induces apoptosis via the Akt pathway and exhibits a synergistic effect with doxorubicin in ovarian cancer cells.

    PubMed

    Ding, Feng; Liu, Tianfeng; Yu, Nina; Li, Shihong; Zhang, Xiaofei; Zheng, Guanghong; Lv, Chunming; Mou, Kai; Xu, Jia; Li, Bo; Wang, Surong; Song, Haibo

    2016-09-01

    Nitidine chloride (NC) exhibits anti-tumor properties in various types of tumor. However, to the best of our knowledge there is no previous evidence of NC involvement in the apoptosis or proliferation of ovarian cancer cells and the underlying molecular mechanisms. The present study aimed to investigate the influence of NC on the viability and apoptosis of ovarian cancer cells and the synergistic effect NC and doxorubicin (DOX) may have on ovarian cancer cells. The viability and proliferation of ovarian cancer cells were examined using a methyl thiazolyl tetrazolium assay and 3H-thymidine incorporation assay. The apoptotic rate of ovarian cancer cells was detected by flow cytometry. The expression of apoptosis‑associated proteins and Akt serine/threonine kinase 1 (Akt) were determined by western blot analysis following NC treatment. The inhibitory effect of NC on the proliferation of ovarian cancer cells was demonstrated in a time and dose‑dependent manner. The pro-apoptotic effect of NC on ovarian cancer cells was also observed. It was determined that NC significantly downregulated the protein expression levels of B‑cell CLL/lymphoma 2 (Bcl-2) and upregulated the expression of Bcl‑2‑associated X protein, p53, caspase‑3 and ‑9. NC suppressed Akt phosphorylation. Additionally, the present study demonstrated that the effect of NC on the proliferation and apoptosis of ovarian cancer cells was Akt‑dependent by using the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt signaling pathway inhibitor, LY294002. NC exhibited a synergistic inhibitory effect on the viability of ovarian cancer cells when combined with DOX. The current study demonstrated that NC inhibited the proliferation and induced the apoptosis of ovarian cancer cells via the Akt signaling pathway and highlighted its potential clinical application for the treatment of ovarian cancer. PMID:27485415

  2. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models

    PubMed Central

    LENGYEL, Ernst; LITCHFIELD, Lacey M.; MITRA, Anirban K.; NIEMAN, Kristin M.; MUKHERJEE, Abir; ZHANG, Yilin; JOHNSON, Alyssa; BRADARIC, Michael; LEE, WooSeok; ROMERO, Iris L.

    2014-01-01

    OBJECTIVE There is increasing pre-clinical evidence indicating that metformin, a medication commonly used for type 2 diabetes, may protect against cancer. Motivated by this emerging evidence we asked two questions: (a) can metformin prevent ovarian cancer growth by altering metabolism, and (b) will metformin increase sensitivity to chemotherapy. STUDY DESIGN The effect of metformin in ovarian cancer was tested in vitro and by using two different mouse models. In vitro, cell lines (n=6) were treated with metformin (10 to 40 mM) or PBS and cellular proliferation and metabolic alterations (AMP-activated protein kinase activity, glycolysis, lipid synthesis) were compared between the two groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/day intraperitoneal (i.p.)) or placebo for 2 weeks followed by i.p. injection of the SKOV3ip1 human ovarian cancer cell line and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-rasG12D/+/PTENfloxP/floxP genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/week i.p. x 7 weeks), metformin (100 mg/kg/day in water x 7 weeks), or paclitaxel plus metformin and tumor volume was compared between treatment groups. RESULTS In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including AMP-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice pre-treated with metformin had 60 % fewer tumor implants compared to controls (p<0.005). In the treatment study, mice treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared to controls (p=0.02); a level of tumor reduction greater than that resulting from either paclitaxel or metformin alone. CONCLUSION Based on these results, we conclude

  3. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    SciTech Connect

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya; An, Byeong Jun; Song, Ho Sueb; Han, Sang Bae; Kim, Jang Heub; Song, Min Jong; Hong, Jin Tae

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  4. Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.

    PubMed

    Kang, Haeyoun; Jeong, Ju-Yeon; Song, Ji-Ye; Kim, Tae Heon; Kim, Gwangil; Huh, Jin Hyung; Kwon, Ah-Young; Jung, Sang Geun; An, Hee Jung

    2016-07-01

    Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence. Gamma-secretase inhibitor (GSI) is a broad-spectrum Notch inhibitor, but it has serious side effects. The efficacy of Notch3-specific inhibition in paclitaxel-resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI. To analyze the effect of Notch3-specific inhibition on paclitaxel-resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel-resistant SKpac cells and parental SKOV3 cells. Expression levels of survival, cell cycle, and apoptosis-related proteins were measured and compared between groups. Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group. In paclitaxel-resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel. Spheroid formation was also significantly reduced. Both Notch3 siRNA-treated cells and GSI-treated cells arrested in the G2/M phase of the cell cycle. Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated. Both GSI and Notch3 siRNA treatment reduced expression of anti-apoptotic proteins (BCL-W, BCL2, and BCL-XL) and increased expression of pro-apoptotic proteins (Bad, Bak, Bim, Bid, and Bax). These results indicate that Notch3-specific inhibition sensitizes paclitaxel-resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI. This approach would be likely to avoid the side effects of broad-spectrum GSI treatment. © 2015 Wiley Periodicals, Inc. PMID:26207830

  5. Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages

    PubMed Central

    Tsuboki, Junko; Fujiwara, Yukio; Horlad, Hasita; Shiraishi, Daisuke; Nohara, Toshihiro; Tayama, Shingo; Motohara, Takeshi; Saito, Yoichi; Ikeda, Tsuyoshi; Takaishi, Kiyomi; Tashiro, Hironori; Yonemoto, Yukihiro; Katabuchi, Hidetaka; Takeya, Motohiro; Komohara, Yoshihiro

    2016-01-01

    It is well known that tumour-associated macrophages (TAMs) play an important role in tumour development by modulating the tumour microenvironment, and targeting of protumour activation or the M2 polarization of TAMs is expected to be an effective therapy for cancer patients. We previously demonstrated that onionin A (ONA), a natural low molecular weight compound isolated from onions, has an inhibitory effect on M2 macrophage polarization. In the present study, we investigated whether ONA had a therapeutic anti-ovarian cancer effect using in vitro and in vivo studies. We found that ONA reduced the extent of ovarian cancer cell proliferation induced by co-culture with human macrophages. In addition, we also found that ONA directly suppressed cancer cell proliferation. A combinatorial effect with ONA and anti-cancer drugs was also observed. The activation of signal transducer and activator of transcription 3 (STAT3), which is involved in cell proliferation and chemo-resistance, was significantly abrogated by ONA in ovarian cancer cells. Furthermore, the administration of ONA suppressed cancer progression and prolonged the survival time in a murine ovarian cancer model under single and combined treatment conditions. Thus, ONA is considered useful for the additional treatment of patients with ovarian cancer owing to its suppression of the protumour activation of TAMs and direct cytotoxicity against cancer cells. PMID:27404320

  6. Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages.

    PubMed

    Tsuboki, Junko; Fujiwara, Yukio; Horlad, Hasita; Shiraishi, Daisuke; Nohara, Toshihiro; Tayama, Shingo; Motohara, Takeshi; Saito, Yoichi; Ikeda, Tsuyoshi; Takaishi, Kiyomi; Tashiro, Hironori; Yonemoto, Yukihiro; Katabuchi, Hidetaka; Takeya, Motohiro; Komohara, Yoshihiro

    2016-01-01

    It is well known that tumour-associated macrophages (TAMs) play an important role in tumour development by modulating the tumour microenvironment, and targeting of protumour activation or the M2 polarization of TAMs is expected to be an effective therapy for cancer patients. We previously demonstrated that onionin A (ONA), a natural low molecular weight compound isolated from onions, has an inhibitory effect on M2 macrophage polarization. In the present study, we investigated whether ONA had a therapeutic anti-ovarian cancer effect using in vitro and in vivo studies. We found that ONA reduced the extent of ovarian cancer cell proliferation induced by co-culture with human macrophages. In addition, we also found that ONA directly suppressed cancer cell proliferation. A combinatorial effect with ONA and anti-cancer drugs was also observed. The activation of signal transducer and activator of transcription 3 (STAT3), which is involved in cell proliferation and chemo-resistance, was significantly abrogated by ONA in ovarian cancer cells. Furthermore, the administration of ONA suppressed cancer progression and prolonged the survival time in a murine ovarian cancer model under single and combined treatment conditions. Thus, ONA is considered useful for the additional treatment of patients with ovarian cancer owing to its suppression of the protumour activation of TAMs and direct cytotoxicity against cancer cells. PMID:27404320

  7. Inhibition of pregnane X receptor pathway contributes to the cell growth inhibition and apoptosis of anticancer agents in ovarian cancer cells.

    PubMed

    Masuyama, Hisashi; Nakamura, Keiichiro; Nobumoto, Etsuko; Hiramatsu, Yuji

    2016-09-01

    Epithelial ovarian cancer remains the most devastating gynecologic cancer with drug resistance and rapid recurrence. Pregnane X receptor (PXR) is a nuclear receptor that affects drug metabolism/efflux and drug-drug interaction through control of multiple drug resistance 1 (MDR1), which implies a major role in multidrug resistance, and other genes. We examined whether the inhibition of PXR-mediated pathway using siRNA interference and an antagonist for PXR could influence the paclitaxel and cisplatin cytotoxicity in ovarian cancer cells. PXR agonists, phthalate and pregnenolone had significant positive effects on cytochrome P450 (CYP) 3A4 expression and PXR-mediated transcription through the CYP3A4 promoter, whereas MDR1 expression and PXR-mediated transcription though the MDR1 promoter were significantly increased in the presence of paclitaxel or cisplatin. Downregulation of PXR suppressed the augmented MDR1 expression and PXR-mediated transcription by PXR ligands, and significantly enhanced cell growth inhibition and apoptosis in the presence of paclitaxel or cisplatin. Additionally, ketoconazole, a PXR antagonist, suppressed the augmented MDR1 expression and PXR-mediated transactivation by paclitaxel and cisplatin, and enhanced cell growth inhibition and apoptosis in their presence. In conclusion, inhibition of PXR-mediated pathways could be a novel means of augmenting sensitivity, or overcoming resistance to anticancer agents for ovarian cancer. PMID:27572875

  8. Ampelopsin reduces the migration and invasion of ovarian cancer cells via inhibition of epithelial-to-mesenchymal transition.

    PubMed

    Liu, Tianfeng; Liu, Peishu; Ding, Feng; Yu, Nina; Li, Shihong; Wang, Surong; Zhang, Xiaofei; Sun, Xiangxiu; Chen, Ying; Wang, Feng; Zhao, Yunhe; Li, Bo

    2015-02-01

    Ampelopsin has displayed anticancer activity in several types of cancers. However, no evidence has been reported for the direct effect of ampelopsin on ovarian cancer cell migration and invasion, and the underling mechanisms have not yet been clearly established. The aim of the present study was to investigate the influence of ampelopsin on the migration and invasion of ovarian cancer. Proliferation and viability of the ovarian cancer cells were detected by MTT assay. Migration and invasion of the cells were detected, respectively, by scratch wound healing assay and Transwell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers were detected at the protein level after stimulation with ampelopsin. Then, the expression levels of NF-κB and p-IκBα were detected with western blot analysis. Meanwhile, an inhibitor of NF-κB was used to investigate the effect of ampelopsin. Finally, the expression of Snail was also detected. Proliferation, migration and invasion of the A2780 cells were all inhibited following the application of ampelopsin. Ampelopsin upregulated E-cadherin and downregulated N-cadherin and vimentin in a concentration- and time-dependent manner. Ampelopsin also exerted its ability to suppress the nuclear translocation of the NF-κB pathway. Administration of the inhibitor BAY11-7082 confirmed the roles of NF-κB in the expression of EMT markers and its transcription factor. These results demonstrated that ampelopsin inhibited EMT and reduced the invasion of ovarian cancer cells via the NF-κB/Snail pathway. PMID:25502786

  9. Ovarian Cancer Stage IV

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IV Add to My Pictures View /Download : ... 1200x1335 View Download Large: 2400x2670 View Download Title: Ovarian Cancer Stage IV Description: Drawing of stage IV shows ...

  10. Ovarian Cancer Stage IIIC

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IIIC Add to My Pictures View /Download : ... 1530x1350 View Download Large: 3060x2700 View Download Title: Ovarian Cancer Stage IIIC Description: Drawing of stage IIIC shows ...

  11. Ovarian Cancer Stage II

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage II Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage II Description: Three-panel drawing of stage ...

  12. Ovarian Cancer Stage I

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage I Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage I Description: Three-panel drawing of stage ...

  13. Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells

    PubMed Central

    Wu, Yi-Hui; Chiu, Wen-Tai; Young, Ming-Jer; Chang, Tzu-Hao; Huang, Yu-Fang; Chou, Cheng-Yang

    2015-01-01

    Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment. PMID:26366215

  14. The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer

    PubMed Central

    Helland, Øystein; Popa, Mihaela; Bischof, Katharina; Gjertsen, Bjørn Tore; McCormack, Emmet; Bjørge, Line

    2016-01-01

    Background In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC. Methods The effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured. Results Panobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment. Conclusions Panobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was

  15. Can Ovarian Cancer Be Found Early?

    MedlinePlus

    ... Topic Signs and symptoms of ovarian cancer Can ovarian cancer be found early? About 20% of ovarian cancers ... cancer in its earliest stage. Ways to find ovarian cancer early Regular women's health exams During a pelvic ...

  16. Efficient Inhibition of Ovarian Cancer by Gelonin Toxin Gene Delivered by Biodegradable Cationic Heparin-polyethyleneimine Nanogels.

    PubMed

    Bai, Yu; Gou, Maling; Yi, Tao; Yang, Li; Liu, Lili; Lin, Xiaojuan; Su, Dan; Wei, Yuquan; Zhao, Xia

    2015-01-01

    The use of toxins for cancer therapy has great promise. Gelonin, a potent plant toxin, causes cell death by inactivating the 60S ribosomal subunit. Recently, we developed a novel gene delivery system using biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels. In the current study, the antitumor activity of a recombinant plasmid expressing gelonin (pGelonin) on human ovarian cancer was assessed. The application of HPEI nanogels, was also evaluated. Gelonin-cDNA was cloned into the pVAX1 plasmid vector and transfected into SKOV3 human ovarian cancer cells using biodegradable cationic HPEI nanogels. The expression of gelonin in vitro and in vivo was confirmed using RT-PCR and western blot analysis. Cell viability and apoptosis were examined using an MTT assay and flow cytometric analysis. For the in vivo study, an SKOV3 intraperitoneal ovarian carcinomatosis model was established, and nude mice were randomly assigned into four groups receiving i.p. administration of pGelonin/HPEI complexes, pVAX/HPEI complexes, HPEI alone and 5% glucose solution. The tumor weight was monitored, and a TUNEL assay and Ki-67 immunohistochemistry were performed to evaluate apoptosis and cell proliferation in the tumor tissue sections, respectively. Gelonin was efficiently expressed in SKOV3 cancer cells in vitro and in vivo using pGelonin incorporated with HPEI nanogels. The pGelonin/HPEI complexes inhibited cell viability and induced apoptosis in the cell culture. Treatment for intraperitoneal carcinomatosis with pGelonin/HPEI complexes reduced the tumor weight by ~58.55% compared to the control groups (P<0.05). The antitumor effect was accompanied by increased apoptosis and reduced cell proliferation (P<0.05). No significant side effects were observed with i.p. administration of the pGelonin/HPEI complexes. Our data indicate that HPEI nanogel-delivered pGelonin may have promising applications against human ovarian cancer. PMID:26005374

  17. Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

    PubMed Central

    2014-01-01

    Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated

  18. Epithelial ovarian cancer: An overview

    PubMed Central

    Desai, Arpita; Xu, Jingyao; Aysola, Kartik; Qin, Yunlong; Okoli, Chika; Hariprasad, Ravipati; Chinemerem, Ugorji; Gates, Candace; Reddy, Avinash; Danner, Omar; Franklin, Geary; Ngozi, Anachebe; Cantuaria, Guilherme; Singh, Karan; Grizzle, William; Landen, Charles; Partridge, Edward E; Rice, Valerie Montgomery; Reddy, E Shyam P; Rao, Veena N

    2014-01-01

    Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions. PMID:25525571

  19. Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

    PubMed Central

    Wang, Sheng-qi; Liu, Shi-ting; Zhao, Bo-xin; Yang, Fu-heng; Wang, Ya-tian; Liang, Qian-ying; Sun, Ya-bin; Liu, Yuan; Song, Zhi-hua; Cai, Yun; Li, Guo-feng

    2015-01-01

    ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in ovarian cancer. Herein, afatinib at nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro (p < 0.05). Combining paclitaxel and afatinib caused tumor regressions and tumor necrosis in A2780T xenografts in vivo. More interestingly, unlike reversible TKIs, afatinib had a distinctive dual-mode action. Afatinib not only inhibited the efflux function of ABCB1, but also attenuated its expression transcriptionally via down-regulation of PI3K/AKT and MAPK/p38-dependent activation of NF-κB. Furthermore, apart from a substrate binding domain, afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533, Gly534, Lys536 and Ala560 sites. Importantly, mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were not correlated with the reversal activity of afatinib on MDR. Given that afatinib is a clinically approved drug, our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer. This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR. PMID:26317651

  20. Huaier Aqueous Extract Inhibits Ovarian Cancer Cell Motility via the AKT/GSK3β/β-Catenin Pathway

    PubMed Central

    Jia, Nan; Yu, Yinhua; Hua, Keqin; Feng, Weiwei

    2013-01-01

    Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3β, inhibition of the phosphorylation of GSK3β on S9, reduction of both cytoplasmic β-catenin expression and nuclear β-catenin translocation, and transcriptional repression of several Wnt/β-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3β, β-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3β/β-catenin signaling pathway. PMID:23667667

  1. Huaier aqueous extract inhibits ovarian cancer cell motility via the AKT/GSK3β/β-catenin pathway.

    PubMed

    Yan, Xiaohui; Lyu, Tianjiao; Jia, Nan; Yu, Yinhua; Hua, Keqin; Feng, Weiwei

    2013-01-01

    Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3β, inhibition of the phosphorylation of GSK3β on S9, reduction of both cytoplasmic β-catenin expression and nuclear β-catenin translocation, and transcriptional repression of several Wnt/β-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3β, β-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3β/β-catenin signaling pathway. PMID:23667667

  2. Ovarian Cancer Statistics

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 22,280 % of All New Cancer Cases 1.3% Estimated Deaths in 2016 14,240 % of All Cancer ... of This Cancer : In 2013, there were an estimated 195,767 women living with ovarian cancer in ...

  3. The tumor suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways

    PubMed Central

    Badgwell, Donna B.; Lu, Zhen; Le, Kim; Gao, Fengqin; Yang, Maojie; Suh, Grace K.; Bao, Jia-Ju; Das, Partha; Andreeff, Michael; Chen, Wenting; Yu, Yinhua; Ahmed, Ahmed Ashour; Liao, Warren S.-L.; Bast, Robert C.

    2011-01-01

    Ovarian cancers migrate and metastasize over the surface of the peritoneal cavity. Consequently, dysregulation of mechanisms that limit cell migration may be particularly important in the pathogenesis of the disease. ARHI is an imprinted tumor suppressor gene that is down regulated in >60% of ovarian cancers and its loss is associated with decreased progression-free survival. ARHI encodes a 26 kDa GTPase with homology to Ras. In contrast to Ras, ARHI inhibits cell growth, but whether it also regulates cell motility has not been previously studied Here we report that re-expression of ARHI decreases motility of IL-6- and EGF-stimulated SKOv3 and Hey ovarian cancer cells, inhibiting both chemotaxis and haptotaxis. ARHI binds and sequesters Stat3 in the cytoplasm, preventing its translocation to the nucleus and localization in focal adhesion complexes. Stat3 siRNA or the JAK2 inhibitor AG490 produced similar inhibition of motility. However, the combination of ARHI expression with Stat3 knockdown or inhibition produced greatest inhibition in ovarian cancer cell migration, consistent with Stat3-dependent and Stat3-independent mechanisms. Consistent with two distinct signaling pathways, knockdown of Stat3 selectively inhibited IL-6-stimulated migration, whereas knockdown of FAK preferentially inhibited EGF-stimulated migration. In EGF-stimulated ovarian cancer cells, re-expression of ARHI inhibited FAKY397 and SrcY416 phosphorylation, disrupted focal adhesions, and blocked FAK-mediated RhoA signaling, resulting in decreased levels of GTP-RhoA. Re-expression of ARHI also disrupted formation of actin stress fibers in a FAK- and RhoA-dependent manner. Thus, ARHI plays a critical and previously uncharacterized role in regulation of ovarian cancer cell migration, exerting inhibitory effects on two distinct signaling pathways. PMID:21643014

  4. CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer

    PubMed Central

    Devapatla, Bharat; Sharma, Ankur; Woo, Sukyung

    2015-01-01

    Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy

  5. CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer.

    PubMed

    Devapatla, Bharat; Sharma, Ankur; Woo, Sukyung

    2015-01-01

    Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy

  6. National Ovarian Cancer Coalition

    MedlinePlus

    ... ovarian cancer Read More View More News Upcoming Events Fabric Extravaganza! September 09, 2016 @ 12:00PM Hosted ... Roxy and Dukes Roadhouse View All Our Upcoming Events Latest from the Blog: Hailey's Story How her ...

  7. STAT3 Decoy Oligodeoxynucleotides-Loaded Solid Lipid Nanoparticles Induce Cell Death and Inhibit Invasion in Ovarian Cancer Cells

    PubMed Central

    Ma, Yanhui; Zhang, Xiaolei; Xu, Xiaoxuan; Shen, Liang; Yao, Yao; Yang, Ziyan; Liu, Peishu

    2015-01-01

    Recent advances in the synthesis of multi-functional nanoparticles have opened up tremendous opportunities for the targeted delivery of genes of interest. Cationic solid lipid nanoparticles (SLN) can efficiently bind nucleic acid molecules and transfect genes in vitro. Few reports have combined SLN with therapy using decoy oligodeoxynucleotides (ODN). In the present study, we prepared SLN to encapsulate STAT3 decoy ODN; then, the properties and in vitro behavior of SLN-STAT3 decoy ODN complexes were investigated. SLN-STAT3 decoy ODN complexes were efficiently taken up by human ovarian cancer cells and significantly suppressed cell growth. Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death. The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR. In addition, SLN-STAT3 decoy ODN complexes inhibited cell invasion by up-regulating E-cadherin expression and down-regulating Snail and MMP-9 expression. These findings confirmed that SLN as STAT3 decoy ODN carriers can induce cell death and inhibit invasion of ovarian cancer cells. We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy. PMID:25923701

  8. Inhibition of Wnt/β-catenin pathway by niclosamide: a therapeutic target for ovarian cancer.

    PubMed

    Arend, Rebecca C; Londoño-Joshi, Angelina I; Samant, Rajeev S; Li, Yonghe; Conner, Michael; Hidalgo, Bertha; Alvarez, Ronald D; Landen, Charles N; Straughn, J Michael; Buchsbaum, Donald J

    2014-07-01

    Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer. PMID:24736023

  9. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    SciTech Connect

    Feng, Xue; Li, Ling; Jiang, Hong; Jiang, Keping; Jin, Ye; Zheng, Jianhua

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  10. 1α,25(OH)₂D₃ Suppresses the Migration of Ovarian Cancer SKOV-3 Cells through the Inhibition of Epithelial-Mesenchymal Transition.

    PubMed

    Hou, Yong-Feng; Gao, Si-Hai; Wang, Ping; Zhang, He-Mei; Liu, Li-Zhi; Ye, Meng-Xuan; Zhou, Guang-Ming; Zhang, Zeng-Li; Li, Bing-Yan

    2016-01-01

    Ovarian cancer is the most lethal gynecological malignancy due to its high metastatic ability. Epithelial-mesenchymal transition (EMT) is essential during both follicular rupture and epithelium regeneration. However, it may also accelerate the progression of ovarian carcinomas. Experimental studies have found that 1α,25-dihydroxyvitamin-D3 [1α,25(OH)₂D₃] can inhibit the proliferation of ovarian cancer cells. In this study, we investigated whether 1α,25(OH)₂D₃ could inhibit the migration of ovarian cancer cells via regulating EMT. We established a model of transient transforming growth factor-β1(TGF-β1)-induced EMT in human ovarian adenocarcinoma cell line SKOV-3 cells. Results showed that, compared with control, 1α,25(OH)₂D₃ not only inhibited the migration and the invasion of SKOV-3 cells, but also promoted the acquisition of an epithelial phenotype of SKOV-3 cells treated with TGF-β1. We discovered that 1α,25(OH)₂D₃ increased the expression of epithelial marker E-cadherin and decreased the level of mesenchymal marker, Vimentin, which was associated with the elevated expression of VDR. Moreover, 1α,25(OH)₂D₃ reduced the expression level of transcription factors of EMT, such as slug, snail, and β-catenin. These results indicate that 1α,25(OH)₂D₃ suppresses the migration and invasion of ovarian cancer cells by inhibiting EMT, implying that 1α,25(OH)₂D₃ might be a potential therapeutic agent for the treatment of ovarian cancer. PMID:27548154

  11. 1α,25(OH)2D3 Suppresses the Migration of Ovarian Cancer SKOV-3 Cells through the Inhibition of Epithelial–Mesenchymal Transition

    PubMed Central

    Hou, Yong-Feng; Gao, Si-Hai; Wang, Ping; Zhang, He-Mei; Liu, Li-Zhi; Ye, Meng-Xuan; Zhou, Guang-Ming; Zhang, Zeng-Li; Li, Bing-Yan

    2016-01-01

    Ovarian cancer is the most lethal gynecological malignancy due to its high metastatic ability. Epithelial-mesenchymal transition (EMT) is essential during both follicular rupture and epithelium regeneration. However, it may also accelerate the progression of ovarian carcinomas. Experimental studies have found that 1α,25-dihydroxyvitamin-D3 [1α,25(OH)2D3] can inhibit the proliferation of ovarian cancer cells. In this study, we investigated whether 1α,25(OH)2D3 could inhibit the migration of ovarian cancer cells via regulating EMT. We established a model of transient transforming growth factor-β1(TGF-β1)-induced EMT in human ovarian adenocarcinoma cell line SKOV-3 cells. Results showed that, compared with control, 1α,25(OH)2D3 not only inhibited the migration and the invasion of SKOV-3 cells, but also promoted the acquisition of an epithelial phenotype of SKOV-3 cells treated with TGF-β1. We discovered that 1α,25(OH)2D3 increased the expression of epithelial marker E-cadherin and decreased the level of mesenchymal marker, Vimentin, which was associated with the elevated expression of VDR. Moreover, 1α,25(OH)2D3 reduced the expression level of transcription factors of EMT, such as slug, snail, and β-catenin. These results indicate that 1α,25(OH)2D3 suppresses the migration and invasion of ovarian cancer cells by inhibiting EMT, implying that 1α,25(OH)2D3 might be a potential therapeutic agent for the treatment of ovarian cancer. PMID:27548154

  12. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

    PubMed Central

    Pépin, David; Sosulski, Amanda; Zhang, Lihua; Wang, Dan; Vathipadiekal, Vinod; Hendren, Katherine; Coletti, Caroline M.; Yu, Aaron; Castro, Cesar M.; Birrer, Michael J.; Gao, Guangping; Donahoe, Patricia K.

    2015-01-01

    To improve ovarian cancer patient survival, effective treatments addressing chemoresistant recurrences are particularly needed. Mullerian inhibiting substance (MIS) has been shown to inhibit the growth of a stem-like population of ovarian cancer cells. We have recently engineered peptide modifications to human MIS [albumin leader Q425R MIS (LRMIS)] that increase production and potency in vitro and in vivo. To test this novel therapeutic peptide, serous malignant ascites from highly resistant recurrent ovarian cancer patients were isolated and amplified to create low-passage primary cell lines. Purified recombinant LRMIS protein successfully inhibited the growth of cancer spheroids in vitro in a panel of primary cell lines in four of six patients tested. Adeno-associated virus (AAV) -delivered gene therapy has undergone a clinical resurgence with a good safety profile and sustained gene expression. Therefore, AAV9 was used as a single i.p. injection to deliver LRMIS to test its efficacy in inhibiting growth of palpable tumors in patient-derived ovarian cancer xenografts from ascites (PDXa). AAV9-LRMIS monotherapy resulted in elevated and sustained blood concentrations of MIS, which significantly inhibited the growth of three of five lethal chemoresistant serous adenocarcinoma PDXa models without signs of measurable or overt toxicity. Finally, we tested the frequency of MIS type II receptor expression in a tissue microarray of serous ovarian tumors by immunohistochemistry and found that 88% of patients bear tumors that express the receptor. Taken together, these preclinical data suggest that AAV9-LRMIS provides a potentially well-tolerated and effective treatment strategy poised for testing in patients with chemoresistant serous ovarian cancer. PMID:26216943

  13. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer.

    PubMed

    Pépin, David; Sosulski, Amanda; Zhang, Lihua; Wang, Dan; Vathipadiekal, Vinod; Hendren, Katherine; Coletti, Caroline M; Yu, Aaron; Castro, Cesar M; Birrer, Michael J; Gao, Guangping; Donahoe, Patricia K

    2015-08-11

    To improve ovarian cancer patient survival, effective treatments addressing chemoresistant recurrences are particularly needed. Mullerian inhibiting substance (MIS) has been shown to inhibit the growth of a stem-like population of ovarian cancer cells. We have recently engineered peptide modifications to human MIS [albumin leader Q425R MIS (LRMIS)] that increase production and potency in vitro and in vivo. To test this novel therapeutic peptide, serous malignant ascites from highly resistant recurrent ovarian cancer patients were isolated and amplified to create low-passage primary cell lines. Purified recombinant LRMIS protein successfully inhibited the growth of cancer spheroids in vitro in a panel of primary cell lines in four of six patients tested. Adeno-associated virus (AAV) -delivered gene therapy has undergone a clinical resurgence with a good safety profile and sustained gene expression. Therefore, AAV9 was used as a single i.p. injection to deliver LRMIS to test its efficacy in inhibiting growth of palpable tumors in patient-derived ovarian cancer xenografts from ascites (PDXa). AAV9-LRMIS monotherapy resulted in elevated and sustained blood concentrations of MIS, which significantly inhibited the growth of three of five lethal chemoresistant serous adenocarcinoma PDXa models without signs of measurable or overt toxicity. Finally, we tested the frequency of MIS type II receptor expression in a tissue microarray of serous ovarian tumors by immunohistochemistry and found that 88% of patients bear tumors that express the receptor. Taken together, these preclinical data suggest that AAV9-LRMIS provides a potentially well-tolerated and effective treatment strategy poised for testing in patients with chemoresistant serous ovarian cancer. PMID:26216943

  14. Drug discovery in ovarian cancer.

    PubMed

    Chase, Dana M; Mathur, Nidhee; Tewari, Krishnansu S

    2010-11-01

    Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligand-binding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of alpha5beta1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed. PMID:20524931

  15. The potassium ion channel opener NS1619 inhibits proliferation and induces apoptosis in A2780 ovarian cancer cells

    SciTech Connect

    Han Xiaobing; Xi Ling; Wang Hui; Huang Xiaoyuan; Ma Xiangyi; Han Zhiqiang; Wu Peng; Ma Xiaoli; Lu Yunping; Wang, Gang Zhou Jianfeng; Ma Ding

    2008-10-17

    Diverse types of voltage-gated potassium (K{sup +}) channels have been shown to be involved in regulation of cell proliferation. The maxi-conductance Ca{sup 2+}-activated K{sup +} channels (BK channels) may play an important role in the progression of human cancer. To explore the role of BK channels in regulation of apoptosis in human ovarian cancer cells, the effects of the specific BK channel activator NS1619 on induction of apoptosis in A2780 cells were observed. Following treatment with NS1619, cell proliferation was measured by MTT assay. Apoptosis of A2780 cells pretreated with NS1619 was detected by agarose gel electrophoresis of cellular DNA and flow cytometry. Our data demonstrate that NS1619 inhibits the proliferation of A2780 cells in a dosage and time dependent manner IC{sub 50} = 31.1 {mu}M, for 48 h pretreatment and induces apoptosis. Western blot analyses showed that the anti-proliferation effect of NS1619 was associated with increased expression of p53, p21, and Bax. These results indicate that BK channels play an important role in regulating proliferation of human ovarian cancer cells and may induce apoptosis through induction of p21{sup Cip1} expression in a p53-dependent manner.

  16. Ixabepilone and Liposomal Doxorubicin in Advanced Ovarian Cancer

    ClinicalTrials.gov

    2016-02-11

    Fallopian Tube Cancer; Female Reproductive Cancer; Recurrent Breast Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer

  17. A novel uPAg-KPI fusion protein inhibits the growth and invasion of human ovarian cancer cells in vitro

    PubMed Central

    ZHAO, LI-PING; XU, TIAN-MIN; KAN, MU-JIE; XIAO, YE-CHEN; CUI, MAN-HUA

    2016-01-01

    Urokinase-type plasminogen activator (uPA) acts by breaking down the basement membrane and is involved in cell proliferation, migration and invasion. These actions are mediated by binding to the uPA receptor (uPAR) via its growth factor domain (GFD). The present study evaluated the effects of uPAg-KPI, a fusion protein of uPA-GFD and a kunitz protease inhibitor (KPI) domain that is present in the amyloid β-protein precursor. Using SKOV-3 cells, an ovarian cancer cell line, we examined cell viability, migration, invasion and also protein expression. Furthermore, we examined wound healing, and migration and invasion using a Transwell assay. Our data showed that uPAg-KPI treatment reduced the viability of ovarian cancer SKOV-3 cells in both a concentration and time-dependent manner by arresting tumor cells at G1/G0 phase of the cell cycle. The IC50 of uPAg-KPI was 0.5 µg/µl after 48 h treatment. At this concentration, uPAg-KPI also inhibited tumor cell colony formation, wound closure, as well as cell migration and invasion capacity. At the protein level, western blot analysis demonstrated that uPAg-KPI exerted no significant effect on the expression of total extracellular signal-regulated kinase (ERK)1/ERK2 and AKT, whereas it suppressed levels of phosphorylated ERK1/ERK2 and AKT. Thus, we suggest that this novel uPAg-KPI fusion protein reduced cell viability, colony formation, wound healing and the invasive ability of human ovarian cancer SKOV-3 cells in vitro by regulating ERK and AKT signaling. Further studies using other cell lines will confirm these findings. PMID:27035617

  18. A novel uPAg-KPI fusion protein inhibits the growth and invasion of human ovarian cancer cells in vitro.

    PubMed

    Zhao, Li-Ping; Xu, Tian-Min; Kan, Mu-Jie; Xiao, Ye-Chen; Cui, Man-Hua

    2016-05-01

    Urokinase-type plasminogen activator (uPA) acts by breaking down the basement membrane and is involved in cell proliferation, migration and invasion. These actions are mediated by binding to the uPA receptor (uPAR) via its growth factor domain (GFD). The present study evaluated the effects of uPAg-KPI, a fusion protein of uPA-GFD and a kunitz protease inhibitor (KPI) domain that is present in the amyloid β-protein precursor. Using SKOV-3 cells, an ovarian cancer cell line, we examined cell viability, migration, invasion and also protein expression. Furthermore, we examined wound healing, and migration and invasion using a Transwell assay. Our data showed that uPAg-KPI treatment reduced the viability of ovarian cancer SKOV-3 cells in both a concentration and time-dependent manner by arresting tumor cells at G1/G0 phase of the cell cycle. The IC50 of uPAg-KPI was 0.5 µg/µl after 48 h treatment. At this concentration, uPAg-KPI also inhibited tumor cell colony formation, wound closure, as well as cell migration and invasion capacity. At the protein level, western blot analysis demonstrated that uPAg-KPI exerted no significant effect on the expression of total extracellular signal-regulated kinase (ERK)1/ERK2 and AKT, whereas it suppressed levels of phosphorylated ERK1/ERK2 and AKT. Thus, we suggest that this novel uPAg-KPI fusion protein reduced cell viability, colony formation, wound healing and the invasive ability of human ovarian cancer SKOV-3 cells in vitro by regulating ERK and AKT signaling. Further studies using other cell lines will confirm these findings. PMID:27035617

  19. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  20. Immunotherapy in ovarian cancer

    PubMed Central

    Mantia-Smaldone, Gina M.; Corr, Bradley; Chu, Christina S.

    2012-01-01

    Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012.1 While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years.1,2 Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer.3,4 By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer. PMID:22906947

  1. miR-339-5p inhibits migration and invasion in ovarian cancer cell lines by targeting NACC1 and BCL6.

    PubMed

    Shan, Weiwei; Li, Jun; Bai, Yang; Lu, Xin

    2016-04-01

    This study aimed to explore the role of miR-339-5p in ovarian cancer. The expression of miR-339-5p in seven ovarian cancer cell lines (Hey, SKOV3, OVCAR5, SKOV3-IP, A2780, CAOV3, and OVCA433) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The miR-339-5p mimic and inhibitor were used to regulate its expression. Migration, invasion, and proliferation were examined. A bioinformatics analysis was used to predict targets, and a dual-luciferase reporter system was applied for validation, along with Western blot verification. Additionally, the association of miR-339-5p and its target genes with ovarian cancer was analyzed based on The Cancer Genome Atlas (TCGA) database. OVCAR5 and SKOV3 had the highest and lowest miR-339-5p expression, respectively. Inhibition of miR-339-5p expression increased the migration and invasion of OVCAR5 cells, while in SKOV3 cells, upregulated miR-339-5p attenuated the migration and invasion ability. Modulation of miR-339-5p had no effect on proliferation. The genes nucleus accumbens associated 1(BEN and BTB (POZ) domain containing) (NACC1) and B cell lymphoma-6 (bcl6) were validated to be targets of miR-339-5p. Clinically, patients with a high expression of NACC1 had a high risk in the survival analysis. miR-339-5p inhibits migration and invasion in ovarian cancer by targeting NACC1 and BCL6. miR-339-5p may be a biomarker of metastasis in ovarian cancer; NACC1 had a predictive value for ovarian cancer progression. PMID:26553360

  2. Grifolin induces autophagic cell death by inhibiting the Akt/mTOR/S6K pathway in human ovarian cancer cells.

    PubMed

    Che, Xiaoxia; Yan, Hong; Sun, Hengzi; Dongol, Samina; Wang, Yilin; Lv, Qingtao; Jiang, Jie

    2016-08-01

    Grifolin, a secondary metabolic product isolated from the mushroom Albatrellus confluence, has been reported to possess antitumor activities in various tumors. To date, no report exists on the role of autophagy in grifolin-treated human ovarian cancer cells. In the present study, we investigated the effect and the mechanism of autophagy in ovarian cancer. Ovarian cancer cell lines A2780 and SKOV3 were treated with grifolin. Cell proliferation was assessed by MTT assay and the autophagic effect was determined using flow cytometry, electron microscopy, immunofluorescence staining and GFP-LC3 puncta formation assay. The expression of autophagy markers and the main autophagy-associated Akt/mTOR/S6K pathway proteins were measured by western blot analysis. MTT assay indicated that grifolin inhibits the proliferation of human ovarian cancer cell lines A2780 and SKOV3. Flow cytometry, electron microscopy, immunofluorescence and GFP-LC3 puncta formation assay proved that grifolin induces autophagic cell death in human ovarian cancer. The results of the western blot analysis suggested that grifolin treatment leads to upregulation of autophagy markers LC3B, Atg7, Beclin-1 along with downregulation of P62. In addition, the proteins of the pathways p-Akt, p-mTOR, p-p70S6K and p-4E-BP1 were downregulated while the total of these proteins remained unaffected. The present study indicated that grifolin could induce autophagic cell death in human ovarian cancer by inhibiting the Akt/mTOR/S6K pathway. PMID:27277722

  3. Denileukin Diftitox Used in Treating Patients With Advanced Refractory Ovarian Cancer, Primary Peritoneal Carcinoma, or Epithelial Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-05-02

    Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  4. Oncolytic reovirus against ovarian and colon cancer.

    PubMed

    Hirasawa, Kensuke; Nishikawa, Sandra G; Norman, Kara L; Alain, Tommy; Kossakowska, Anna; Lee, Patrick W K

    2002-03-15

    Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy. PMID:11912142

  5. Do We Know What Causes Ovarian Cancer?

    MedlinePlus

    ... ovarian cancer be prevented? Do we know what causes ovarian cancer? We don’t yet know exactly what causes ... Another theory is that male hormones (androgens) can cause ovarian cancer. Researchers have made great progress in understanding how ...

  6. Epac1 knockdown inhibits the proliferation of ovarian cancer cells by inactivating AKT/Cyclin D1/CDK4 pathway in vitro and in vivo.

    PubMed

    Gao, Meng; Ma, Yanyan; Bast, Robert C; Li, Yue; Wan, Lu; Liu, Yanping; Sun, Yingshuo; Fang, Zhenghui; Zhang, Lining; Wang, Xiaoyan; Wei, Zengtao

    2016-07-01

    Ovarian cancer is the leading cause of death among gynecological malignancies, and high grade serous ovarian carcinoma is the most common and most aggressive subtype. Recently, it was demonstrated that cAMP mediates protein kinase A-independent effects through Epac (exchange protein directly activated by cAMP) proteins. Epac proteins, including Epac1 and Epac2, are implicated in several diverse cellular responses, such as insulin secretion, exocytosis, cellular calcium handling and formation of cell-cell junctions. Several reports document that Epac1 could play vital roles in promoting proliferation, invasion and migration of some cancer cells. However, the expression levels and roles of Epac1 in ovarian cancer have not been investigated. In the present study, we detected the expression levels of Epac1 mRNA and protein in three kinds of ovarian cancer cells SKOV3, OVCAR3 and CAOV3. Furthermore, the effect of Epac1 knockdown on the proliferation and apoptosis of SKOV3 and OVCAR3 cells was evaluated in vitro and in vivo. The results showed that there was higher expression of Epac1 mRNA and protein in SKOV3 and OVCAR3 cells. Epac1 knockdown inhibited the proliferation of SKOV3 and OVCAR3 cells in vitro and in vivo. Decreased proliferation may be due to downregulation of Epac1-induced G1 phase arrest by inactivating the AKT/Cyclin D1/CDK4 pathway, but not to alterations in the MAPK pathway or to apoptosis. Taken together, our data provide new insight into the essential role of Epac1 in regulating growth of ovarian cancer cells and suggest that Epac1 might represent an attractive therapeutic target for treatment of ovarian cancer. PMID:27277757

  7. The milk-derived hexapeptide PGPIPN inhibits the invasion and migration of human ovarian cancer cells by regulating the expression of MTA1 and NM23H1 genes.

    PubMed

    Zhao, Mengjing; Wei, Cai; Yang, Xue; Zhou, Juan; Wang, Jing; Gu, Fang; Lei, Ting; Qin, Yide

    2016-04-01

    Some bioactive peptides derived from natural resources or synthesized by rational design have been proved to have very good anticancer effect. We studied the inhibition of PGPIPN, a hexapeptide derived from bovine β-casein, on the invasion and metastasis of human ovarian cancer cells in vitro and its molecular mechanism. The human ovarian cancer cells studied include the cell line SKOV3 as well as the primary ovarian cancer cells from ovarian tumor tissues of 37 patients at initial debulking surgery, diagnosed as serous ovarian adenocarcinoma. We showed that PGPIPN inhibited the invasion of ovarian cancer cells with Transwell chamber assay, the migration of ovarian cancer cells with cell scratch assay and colony formation of ovarian cancer cells. The expression (mRNAs and proteins) of genes relevant to invasion and metastasis, MTA1, and NM23H1 were analyzed by real-time PCR and western blotting. PGPIPN repressed the expression of MTA1, and promoted NM23H1. The effects of PGPIPN were dose-dependent. Thus, our study suggests that PGPIPN is a potential therapeutic agent for adjuvant therapy of human malignant ovarian tumors. PMID:26893013

  8. Anti-Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines

    PubMed Central

    Jung, Yeon Soo; Kim, Hee Jung; Seo, Seok Kyo; Choi, Young Sik; Nam, Eun Ji; Kim, Sunghoon; Kim, Sang Wun; Han, Hyuck Dong; Kim, Jae Wook

    2016-01-01

    Purpose This study aimed to investigate whether Müllerian 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. PMID:26632380

  9. The Chinese herbs Scutellaria baicalensis and Fritillaria cirrhosa target NFκB to inhibit proliferation of ovarian and endometrial cancer cells.

    PubMed

    Kavandi, Leyla; Lee, Laura R; Bokhari, Amber A; Pirog, John E; Jiang, Yongping; Ahmad, Kashif A; Syed, Viqar

    2015-05-01

    The herbs Scutellaria baicalensis (SB) and Fritillaria cirrhosa (FC) are widely used in Chinese medicine to treat several aliments and as an adjuvant to chemotherapy of lung cancer. No information is available regarding the two herbs' influence on ovarian and endometrial cancer. To fill this data gap we compared cell growth responses to SB and FC in ovarian and endometrial cancer cell lines. Dose-dependent cell growth inhibition was observed following higher doses in all cell lines while lower doses stimulated growth in only endometrial cell lines. Higher doses of SB and FC significantly decreased cell growth on soft agar and decreased the invasive potential of cancer cells. Treatment of cells with both herbs resulted in activation of caspase-3, G0 /G1 phase cell cycle arrest, downregulation of cyclins D1 and D3 and induction of p27. Both herbs decreased NFκB DNA binding, reduced expression of phosphorylated IκBα, abrogated NFκB activation, and downregulated NFκB-regulated metastasis-promoting proteins in cancer cells. Furthermore, knockdown of NFκB attenuated SB- and FC-induced cell growth inhibition. These results suggest that inhibition of NFκB activation may be an important mechanism for growth suppression by SB and FC. Data indicate that these herbs may represent a new source of agents for NFκB inhibition in cancer therapy. PMID:24249479

  10. Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers.

    PubMed

    Creighton, Chad J; Fountain, Michael D; Yu, Zhifeng; Nagaraja, Ankur K; Zhu, Huifeng; Khan, Mahjabeen; Olokpa, Emuejevoke; Zariff, Azam; Gunaratne, Preethi H; Matzuk, Martin M; Anderson, Matthew L

    2010-03-01

    MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including the cell cycle regulator E2F2. MIR31 and CDKN2A, which encode p14(ARF) and p16(INK4A), are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14(ARF) promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14(ARF) to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14(ARF)-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially affecting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31. PMID:20179198

  11. The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells

    PubMed Central

    Goncharenko-Khaider, N; Lane, D; Matte, I; Rancourt, C; Piché, A

    2010-01-01

    Epithelial ovarian cancer (EOC) cells often show increased activity of the PI3K/Akt pathway. In addition, we have previously shown that EOC ascites induce Akt activation in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive EOC cell line, CaOV3, leading to TRAIL-mediated apoptosis inhibition. In this study, we investigated the role of Akt in intrinsic resistance to TRAIL, which is common in EOC cells. We report that Akt activation reduces the sensitivity of EOC cells to TRAIL. TRAIL-resistant SKOV3ip1 and COV2 cells were sensitized to TRAIL-induced apoptosis by PI3K or Akt inhibitors although inhibition of PI3K/Akt signaling pathway did not interfere with the recruitment and processing of caspase-8 to the death-inducing signaling complex. Conversely, overexpression of Akt1 in TRAIL-sensitive cells promoted resistance to TRAIL. Although the fact that TRAIL-induced caspase-8 activation was observed in both sensitive and resistant cell lines, Bid cleavage occurred only in sensitive cells or in SKOV3ip1 cells treated with LY294002. Bid expression was low in resistant cells and Akt activation downregulated its expression. Depletion of Bid by siRNA in OVCAR3 cells was associated with a decrease in TRAIL-mediated apoptosis. Overexpression of Bid only in SKOV3ip1 cells enhanced TRAIL-induced apoptosis. Simultaneous blockade of Akt pathway further increased TRAIL-induced apoptosis. Thus, Akt acts upstream of mitochondria and inhibits TRAIL-induced apoptosis by decreasing Bid protein levels and possibly inhibiting its cleavage. PMID:20661217

  12. Anti-Tumor Effect of Pinus massoniana Bark Proanthocyanidins on Ovarian Cancer through Induction of Cell Apoptosis and Inhibition of Cell Migration

    PubMed Central

    Liu, Jia; Bai, Jing; Jiang, Guoqiang; Li, Xinli; Wang, Jing; Wu, Dachang; Owusu, Lawrence; Zhang, Ershao; Li, Weiling

    2015-01-01

    Pinus massoniana bark proanthocyanidins (PMBPs), an active component isolated from Pinus massoniana bark, has been reported to possess a wide range of biochemical properties. Here, we investigated the anti-tumor effect of PMBPs on ovarian cancer. The results indicated that PMBPs significantly reduced the growth of ovarian cancer cells and induced dose-dependent apoptosis. The underlying mechanisms involved were elucidated to include the loss of mitochondrial membrane potential, down-regulation of the anti-apoptotic protein Bcl-2 and the activation of Caspase 3/9, suggesting that PMBPs triggered apoptosis through activation of mitochondria-associated apoptotic pathway. In addition, wound healing and transwell chamber assays revealed that PMBPs could suppress migration and invasion of ovarian cancer cells. PMBPs dramatically inhibited MMP-9 activity and expression, blocked the activity of NFκB and the activation of ERK1/2 and p38 MAPK. Our findings suggest that PMBPs has the potential to be developed as an anti-tumor drug for ovarian cancer treatment and/ or disease management. PMID:26539720

  13. MicroRNAs 125a and 125b inhibit ovarian cancer cells through post-transcriptional inactivation of EIF4EBP1

    PubMed Central

    Jeon, Myung Jae

    2016-01-01

    The aim of the present study was to identify the specific miRNAs involved in regulation of EIF4EBP1 expression in ovarian cancer and to define their biological function. miRNA mimics and miRNA inhibitors were used in quantitative PCR, western blotting, and luciferase reporter assays to assess cell migration, invasiveness, and viability. miR-125a and miR-125b were downregulated in ovarian cancer tissue and cell lines relative to healthy controls. Increased expression of miR-125a and miR-125b inhibited invasion and migration of SKOV3 and OVCAR-429 ovarian cancer cells and was associated with a decrease in EIF4EBP1 expression. The inverse relationship between miR-125a and miR-125b was corroborated by cotransfection of a luciferase reporter plasmid. Furthermore, miR-125a and miR-125b caused apoptosis and decreased cell viability and migration in an apparently EIF4EBP1-directed manner. Collectively, these results indicate that miR-125a and miR-125b are important posttranscriptional regulators of EIF4EBP1 expression, providing rationale for new therapeutic approaches to suppress tumour invasion and migration using miR-125a, miR-125b, or their mimics for the treatment of ovarian cancer. PMID:26646586

  14. The Cancer Genome Atlas ovarian cancer analysis

    Cancer.gov

    An analysis of genomic changes in ovarian cancer has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Re

  15. Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells

    PubMed Central

    Teng, Pang-ning; Bateman, Nicholas W.; Darcy, Kathleen M.; Hamilton, Chad A.; Maxwell, George Larry; Bakkenist, Christopher J.; Conrads, Thomas P.

    2015-01-01

    Objective Significant reductions in gynecologic (GYN) cancer mortality and morbidity require treatments that prevent and reverse resistance to chemotherapy and radiation. The objective of this study was to determine if pharmacologic inhibition of key DNA damage response kinases in GYN cancers would enhance cell killing by platinum-based chemotherapy and radiation. Methods A panel of human ovarian, endometrial and cervical cancer cell lines were treated with platinum drugs or ionizing radiation (IR) along with small molecule pharmacological kinase inhibitors of Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR). Results Pharmacologic inhibition of ATR significantly enhanced platinum drug response in all GYN cancer cell lines tested, whereas inhibition of ATM did not enhance the response to platinum drugs. Co-inhibition of ATM and ATR did not enhance platinum kill beyond that observed by inhibition of ATR alone. By contrast, inhibiting either ATR or ATM enhanced the response to IR in all GYN cancer cells, with further enhancement achieved with co-inhibition. Conclusions These studies highlight actionable mechanisms operative in GYN cancer cells with potential to maximize response of platinum agents and radiation in newly diagnosed as well as recurrent gynecologic cancers. PMID:25560806

  16. Inhibition of the long non-coding RNA MALAT1 suppresses tumorigenicity and induces apoptosis in the human ovarian cancer SKOV3 cell line

    PubMed Central

    LIU, SHIPING; JIANG, XUAN; LI, WEIHUA; CAO, DONGYAN; SHEN, KENG; YANG, JIAXIN

    2016-01-01

    Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a 8,000 nucleotide-long, spliced non-coding RNA, which has been reported to be deregulated in several tumors. However, to the best of our knowledge, the role of MALAT1 in ovarian cancer has not been previously investigated. The aim of the present study was to investigate the effect of MALAT1 inhibition on the tumorigenity of SKOV3 cells. First, stable MALAT1-knockdown ovarian cancer cells and control cells were established using lentivirus-mediated artificial micro RNA interference in order to investigate the effect of MALAT1 inhibition on cell viability, clonability, migration, invasion and apoptosis in vitro. In addition, the effect of MALAT1 on cell growth in nude mice was assessed. To identify the possible targets of MALAT1, total RNA was extracted from MALAT1-knockdown cells and control cells and a microarray analysis was performed. The results showed that MALAT1 inhibition significantly suppressed tumorigenity in vitro and in vivo (P<0.01). Compared with the control cells, 921 genes in the MALAT1-knockdown cells were deregulated by at least two-fold. The results of the reverse transcription-quantitative polymerase chain reaction showed that 19 of the 20 genes selected for validation confirmed the deregulation indicated by the microarray analysis. The findings define a major oncogenic role for MALAT1, which may offer an attractive novel target for therapeutic intervention in ovarian cancer. PMID:27313681

  17. Can Ovarian Cancer Be Prevented?

    MedlinePlus

    ... ovaries removed with your doctor. Prevention strategies for women with a family history of ovarian cancer or BRCA mutation If your ... what the results mean to you. For some women with a strong family history of ovarian cancer, knowing they do not have ...

  18. Oncolytic virotherapy for ovarian cancer

    PubMed Central

    Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant

    2012-01-01

    In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology. PMID:25977900

  19. SMIFH2-mediated mDia formin functional inhibition potentiates chemotherapeutic targeting of human ovarian cancer spheroids.

    PubMed

    Ziske, Megan A; Pettee, Krista M; Khaing, MaNada; Rubinic, Kaitlin; Eisenmann, Kathryn M

    2016-03-25

    Due to a lack of effective screening or prevention protocol for epithelial ovarian cancer (EOC), there is a critical unmet need to develop therapeutic interventions for EOC treatment. EOC metastasis is unique. Initial dissemination is not primarily hematogenous, yet is facilitated through shedding of primary tumor cells into the peritoneal fluid and accumulating ascites. Increasingly, isolated patient spheroids point to a clinical role for spheroids in EOC metastasis. EOC spheroids are highly invasive structures that disseminate upon peritoneal mesothelium, and visceral tissues including liver and omentum. Selection for this subset of chemoresistant EOC cells could influence disease progression and/or recurrence. Thus, targeting spheroid integrity/structure may improve the chemotherapeutic responsiveness of EOC. We discovered a critical role for mammalian Diaphanous (mDia)-related formin-2 in maintaining EOC spheroid structure. Both mDia2 and the related mDia1 regulate F-actin networks critical to maintain cell-cell contacts and the integrity of multi-cellular epithelial sheets. We investigated if mDia2 functional inhibition via a small molecule inhibitor SMIFH2 combined with chemotherapeutics, such as taxol and cisplatin, inhibits the viability of EOC monolayers and clinically relevant spheroids. SMIFH2-mediated mDia formin inhibition significantly reduced both ES2 and Skov3 EOC monolayer viability while spheroid viability was minimally impacted only at the highest concentrations. Combining either cisplatin or taxol with SMIFH2 did not significantly enhance the effects of either drug alone in ES2 monolayers, while Skov3 monolayers treated with taxol or cisplatin and SMIFH2 showed significant additive inhibition of viability. ES2 spheroids were highly responsive with clear additive anti-viability effects with dual taxol or cisplatin when combined with SMIFH2 treatments. While combined taxol with SMIFH2 in spheroids showed an additive effect relative to single

  20. Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

    ClinicalTrials.gov

    2016-03-17

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  1. SNAIL gene inhibited by hypoxia-inducible factor 1α (HIF-1α) in epithelial ovarian cancer.

    PubMed

    Zhang, Pengnan; Liu, Yanmei; Feng, Youji; Gao, Shujun

    2016-09-01

    The aim of this study was to investigate the relationship between HIF-1α and SNAIL gene expression in the epithelial ovarian cancer (EOC) cell line. EOC cells were treated with hypoxia, hypoxia combined with rapamycin, and control. The expression of HIF-1α and E-cad were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. The gene expression of SNAIL was studied by RT-PCR and real-time PCR. RNA interference technology was used to determine the relationship between HIF-1α and SNAIL. The present study indicated that the HIF-1α protein was expressed and increased in EOC cell line. SNAIL mRNA was found to increase and E-cad expression decreased with the time of hypoxia prolonged. Hypoxia increased invasion abilities of EOC cell line, but compared with cells exposed to hypoxia, the change of invasive ability of cells with rapamycin had no effect. The expression of HIF-1α protein and SNAIL mRNA could be inhibited gradually by rapamycin. siRNA of HIF-1α could suppress the expression of SNAIL while siRNA of SNAIL had no influence on HIF-1α protein expression. HIF-1α may be the upstream of the SNAIL gene in EOC. Our data suggested that HIF-1α might be an upregulator of the SNAIL gene and HIF-1α-SNAIL-E-cad pathway may play an important role in EOC invasion and metastasis. PMID:27044634

  2. Selective inhibition of tumor cell associated Vacuolar-ATPase 'a2' isoform overcomes cisplatin resistance in ovarian cancer cells.

    PubMed

    Kulshrestha, Arpita; Katara, Gajendra K; Ginter, Jordyn; Pamarthy, Sahithi; Ibrahim, Safaa A; Jaiswal, Mukesh K; Sandulescu, Corina; Periakaruppan, Ramayee; Dolan, James; Gilman-Sachs, Alice; Beaman, Kenneth D

    2016-06-01

    Development of resistance to platinum compounds significantly hinders successful ovarian cancer (OVCA) treatment. In tumor cells, dysregulated pH gradient across cell membranes is a key physiological mechanism of metastasis/chemo-resistance. These pH alterations are mediated by aberrant activation of key multi-subunit proton pumps, Vacuolar-ATPases (V-ATPases). In tumor cells, its 'a2' isoform (V-ATPase-V0a2) is a component of functional plasma-membrane complex and promotes tumor invasion through tumor-acidification and immuno-modulation. Its involvement in chemo-resistance has not been studied. Here, we show that V-ATPase-V0a2 is over-expressed in acquired-cisplatin resistant OVCA cells (cis-A2780/cis-TOV112D). Of all the 'a' subunit isoforms, V-ATPase-V0a2 exhibited an elevated expression on plasma membrane of cisplatin-resistant cells compared to sensitive counterparts. Immuno-histochemistry revealed V-ATPase-V0a2 expression in both low grade (highly drug-resistant) and high grade (highly recurrent) human OVCA tissues indicating its role in a centralized mechanism of tumor resistance. In cisplatin resistant cells, shRNA mediated inhibition of V-ATPase-V0a2 enhanced sensitivity towards both cisplatin and carboplatin. This improved cytotoxicity was mediated by enhanced cisplatin-DNA-adduct formation and suppressed DNA-repair pathway, leading to enhanced apoptosis. Suppression of V0a2 activity strongly reduced cytosolic pH in resistant tumor cells, which is known to enhance platinum-associated DNA-damage. As an indicator of reduced metastasis and chemo-resistance, in contrast to plasma membrane localization, a diffused cytoplasmic localization of acidic vacuoles was observed in V0a2-knockdown resistant cells. Interestingly, pre-treatment with monoclonal V0a2-inhibitory antibody enhanced cisplatin cytotoxicity in resistant cells. Taken together, our findings suggest that the isoform specific inhibition of V-ATPase-V0a2 could serve as a therapeutic strategy for chemo

  3. Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells

    PubMed Central

    Ding, Yong-Hui; Zhou, Zhi-Wei; Ha, Chun-Fang; Zhang, Xue-Yu; Pan, Shu-Ting; He, Zhi-Xu; Edelman, Jeffrey L; Wang, Dong; Yang, Yin-Xue; Zhang, Xueji; Duan, Wei; Yang, Tianxin; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5′-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer

  4. Emblica officinalis Extract Induces Autophagy and Inhibits Human Ovarian Cancer Cell Proliferation, Angiogenesis, Growth of Mouse Xenograft Tumors

    PubMed Central

    De, Alok; De, Archana; Papasian, Chris; Hentges, Shane; Banerjee, Snigdha; Haque, Inamul; Banerjee, Sushanta K.

    2013-01-01

    Patients with ovarian cancer (OC) may be treated with surgery, chemotherapy and/or radiation therapy, although none of these strategies are very effective. Several plant-based natural products/dietary supplements, including extracts from Emblicaofficinalis (Amla), have demonstrated potent anti-neoplastic properties. In this study we determined that Amla extract (AE) has anti-proliferative effects on OC cells under both in vitro and in vivo conditions. We also determined the anti-proliferative effects one of the components of AE, quercetin, on OC cells under in vitro conditions. AE did not induce apoptotic cell death, but did significantly increase the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. Quercetin also increased the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also significantly reduced the expression of several angiogenic genes, including hypoxia-inducible factor 1α (HIF-1α) in OVCAR3 cells. AE acted synergistically with cisplatin to reduce cell proliferation and increase expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also had anti-proliferative effects and induced the expression of the autophagic proteins beclin1 and LC3B-II in mouse xenograft tumors. Additionally, AE reduced endothelial cell antigen – CD31 positive blood vessels and HIF-1α expression in mouse xenograft tumors. Together, these studies indicate that AE inhibits OC cell growth both in vitro and in vivo possibly via inhibition of angiogenesis and activation of autophagy in OC. Thus AE may prove useful as an alternative or adjunct therapeutic approach in helping to fight OC. PMID:24133573

  5. Proteasome Inhibition Increases Recruitment of IκB Kinase β (IKKβ), S536P-p65, and Transcription Factor EGR1 to Interleukin-8 (IL-8) Promoter, Resulting in Increased IL-8 Production in Ovarian Cancer Cells*

    PubMed Central

    Singha, Bipradeb; Gatla, Himavanth Reddy; Manna, Subrata; Chang, Tzu-Pei; Sanacora, Shannon; Poltoratsky, Vladimir; Vancura, Ales; Vancurova, Ivana

    2014-01-01

    Proinflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) contributes to ovarian cancer progression through its induction of tumor cell proliferation, survival, angiogenesis, and metastasis. Proteasome inhibition by bortezomib, which has been used as a frontline therapy in multiple myeloma, has shown only limited effectiveness in ovarian cancer and other solid tumors. However, the responsible mechanisms remain elusive. Here, we show that proteasome inhibition dramatically increases the IL-8 expression and release in ovarian cancer cells. The responsible mechanism involves an increased nuclear accumulation of IκB kinase β (IKKβ) and an increased recruitment of the nuclear IKKβ, p65-phosphorylated at Ser-536, and the transcription factor early growth response-1 (EGR-1) to the endogenous IL-8 promoter. Coimmunoprecipitation studies identified the nuclear EGR-1 associated with IKKβ and with p65, with preferential binding to S536P-p65. Both IKKβ activity and EGR-1 expression are required for the increased IL-8 expression induced by proteasome inhibition in ovarian cancer cells. Interestingly, in multiple myeloma cells the IL-8 release is not increased by bortezomib. Together, these data indicate that the increased IL-8 release may represent one of the underlying mechanisms responsible for the decreased effectiveness of proteasome inhibition in ovarian cancer treatment and identify IKKβ and EGR-1 as potential new targets in ovarian cancer combination therapies. PMID:24337575

  6. Epigenetic targeting of ovarian cancer stem cells.

    PubMed

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P; Matei, Daniela

    2014-09-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID:25035395

  7. "Incessant ovulation" and ovarian cancer.

    PubMed

    Casagrande, J T; Louie, E W; Pike, M C; Roy, S; Ross, R K; Henderson, B E

    1979-07-28

    A case-control study of 150 ovarian cancer patients under the age of 50 and individually matched controls was done to study the influence of fertility and oral contraceptive use on the risk of ovarian cancer. The risk decreased with increasing numbers of live births, with increasing numbers of incomplete pregnancies, and with the use of oral contraceptives. These three factors can be amalgamated into a single index of protection--"protected time"--by considering them all as periods of anovulation. The complement of protected time--viz., "ovulatory age", the period between menarche and diagnosis of ovarian cancer (or cessation of menses) minus "protected time"--was strongly related to risk of ovarian cancer. Other factors found to be associated with increased ovarian cancer risk were obesity, cervical polyps, and gallbladder disease. Women who had an "immediate" intolerance to oral contraceptive use had a fourfold increased risk of ovarian cancer. 7 patients, but no controls, could recall a family history of ovarian cancer. PMID:89281

  8. Disulfiram/copper causes redox-related proteotoxicity and concomitant heat shock response in ovarian cancer cells that is augmented by auranofin-mediated thioredoxin inhibition

    PubMed Central

    Papaioannou, Margarita; Mylonas, Ioannis; Kast, Richard E.; Brüning, Ansgar

    2014-01-01

    A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called drug repositioning. Recurrent ovarian cancer is a nearly incurable malignancy for which new and effective treatments are urgently needed. The alcohol-deterring drug disulfiram has been shown to cause preferential cell death in a variety of cancer cells. In this study, it is shown that disulfiram mediates effective cell death in ovarian cancer cells by promoting a pro-oxidative intracellular environment in a copper-dependent mechanism. Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32. The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates. Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic disulfiram and the anti-rheumatic auranofin, may be of interest for the treatment of recurrent and genotoxic drug-resistant ovarian cancer by inducing a proteotoxic cell death mechanism. PMID:25593981

  9. RNAi-mediated knockdown of the CLN3 gene inhibits proliferation and promotes apoptosis in drug-resistant ovarian cancer cells

    PubMed Central

    MAO, DONGWEI; CHE, JIANHUA; HAN, SHIYU; ZHAO, HONGHUI; ZHU, YUMEI; ZHU, HONG

    2015-01-01

    CLN3 is a recently identified anti-apoptotic gene, which has been demonstrated to be highly expressed in a diverse range of cancer cell lines, including ovarian cancer. In the present study, RNA interference, mediated by a lentivirus expressing CLN3 short hairpin RNA (shRNA) was utilized to knockdown the expression of CLN3 in the A2780 human ovarian cancer cell line, and its cisplatin-resistant and carboplatin-resistant sublines, A2780/DDP and A2780/CBP cells. It was revealed that the mRNA and protein expression levels of CLN3 were significantly reduced in the CLN3-specific shRNA-transduced cells, compared with the untransduced and control shRNA-transduced cells. In addition, specific knockdown of CLN3 in these cells inhibited cell proliferation and led to cell cycle arrest at the G0/G1 phase, with eventual apoptosis. CLN3 knockdown caused increases in the levels of Bax, FAX, cleaved-caspase 3, cleaved-caspase 8 and cleaved-RARP, but decreased the level of Bcl-2. Finally, it was observed that CLN3 depletion markedly reduced the half maximum inhibitory concentration in the A2780/DDP and A2780/CBP cells. Taken together, these data suggested that CLN3 is involved in tumorigenesis and drug resistance in ovarian cancer, and may serve as a promising therapeutic target for its treatment. PMID:26299671

  10. Disulfiram/copper causes redox-related proteotoxicity and concomitant heat shock response in ovarian cancer cells that is augmented by auranofin-mediated thioredoxin inhibition.

    PubMed

    Papaioannou, Margarita; Mylonas, Ioannis; Kast, Richard E; Brüning, Ansgar

    2014-01-01

    A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called drug repositioning. Recurrent ovarian cancer is a nearly incurable malignancy for which new and effective treatments are urgently needed. The alcohol-deterring drug disulfiram has been shown to cause preferential cell death in a variety of cancer cells. In this study, it is shown that disulfiram mediates effective cell death in ovarian cancer cells by promoting a pro-oxidative intracellular environment in a copper-dependent mechanism. Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32. The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates. Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic disulfiram and the anti-rheumatic auranofin, may be of interest for the treatment of recurrent and genotoxic drug-resistant ovarian cancer by inducing a proteotoxic cell death mechanism. PMID:25593981

  11. Polyglutamate Paclitaxel and Carboplatin in Treating Patients With Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-05-07

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  12. Tumor infiltrating lymphocytes in ovarian cancer

    PubMed Central

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. PMID:25894333

  13. ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells

    PubMed Central

    Luo, N; Guo, J; Chen, L; Yang, W; Qu, X; Cheng, Z

    2016-01-01

    Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of ovarian cancer. ARHGAP10 is a member of RhoGAP proteins and inactivates Cdc42 by converting GTP-bound form to GDP-bound form. Here, we aimed to evaluate ARHGAP10 expression profile and functions in ovarian cancer. The decreased expression of ARHGAP10 was found in 77.3% (58/75) of ovarian cancer tissues, compared with their non-tumorous counterparts. Furthermore, overall survival in ovarian cancer patients with higher expression of ARHGAP10 was longer than those with lower expression. Ectopic expression of ARHGAP10 in two ovarian cancer cell lines with lower expression of ARHGAP10 (A2780 and HO-8910) dramatically suppressed cell proliferation in vitro. In nude mice, its stable overexpression significantly inhibited the tumorigenicity of A2780 cells. We further demonstrated that overexpression of ARHGAP10 significantly inhibited cell adhesion, migration and invasion, resulted in cell arrest in G1 phase of cell cycle and a significant increase of apoptosis. Moreover, ARHGAP10 interacted with Cdc42 and overexpression of ARHGAP10 inhibited the activity of Cdc42 in A2780 cells. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that KEGG cell cycle, replication and base excision repair (BER) pathways were correlatively with the ARHGAP10 expression, which was further confirmed in ovarian cancer cells by western blotting. Hence, ARHGAP10 may serve as a tumor suppressor through inactivating Cdc42, as well as inhibiting cell cycle, replication and BER pathways. Our data suggest an important role of ARHGAP10 in the molecular etiology of cancer and implicate the potential application of ARHGAP10 in cancer therapy. PMID:27010858

  14. Inhibitory Effect of Baicalin and Baicalein on Ovarian Cancer Cells

    PubMed Central

    Chen, Jianchu; Li, Zhaoliang; Chen, Allen Y.; Ye, Xingqian; Luo, Haitao; Rankin, Gary O.; Chen, Yi Charlie

    2013-01-01

    Ovarian cancer is one of the primary causes of death for women all through the Western world. Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants and are thought to have antioxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45–55 μM for baicalin and 25–40 μM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 μM for baicalin and 68 μM for baicalein. Baicalin decreased expression of VEGF (20 μM), cMyc (80 μM), and NFkB (20 μM); baicalein decreased expression of VEGF (10 μM), HIF-1α (20 μM), cMyc (20 μM), and NFkB (40 μM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB. Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers. PMID:23502466

  15. What Are the Key Statistics about Ovarian Cancer?

    MedlinePlus

    ... factors for ovarian cancer? What are the key statistics about ovarian cancer? The American Cancer Society estimates ... ovarian cancer is about 1 in 100. (These statistics don’t count low malignant potential ovarian tumors.) ...

  16. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression

    PubMed Central

    Skubitz, Amy P.N.; Taras, Elizabeth P.; Boylan, Kristin L.M.; Waldron, Nate N.; Oh, Seunguk; Panoskaltsis-Mortari, Angela; Vallera, Daniel A.

    2013-01-01

    Objectives While most women with ovarian cancer will achieve complete remission after treatment, the majority will relapse within two years, highlighting the need for novel therapies. Cancer stem cells (CSC) have been identified in ovarian cancer and most other carcinomas as a small population of cells that can self-renew. CSC are more chemoresistant and radio-resistant than the bulk tumor cells; it is likely that CSC are responsible for relapse, the major problem in cancer treatment. CD133 has emerged as one of the most promising markers for CSC in ovarian cancer. The hypothesis driving this study is that despite their low numbers in ovarian cancer tumors, CSC can be eradicated using CD133 targeted therapy and tumor growth can be inhibited. Methods Ovarian cancer cell lines were evaluated using flow cytometry for expression of CD133. In vitro viability studies with an anti-CD133 targeted toxin were performed on one of the cell lines, NIH:OVCAR5. The drug was tested in vivo using a stably transfected luciferase-expressing NIH:OVCAR5 subline in nude mice, so that tumor growth could be monitored by digital imaging in real time. Results Ovarian cancer cell lines showed 5.6% to 16.0% CD133 expression. dCD133KDEL inhibited the in vitro growth of NIH:OVCAR5 cells. Despite low numbers of CD133-expressing cells in the tumor population, intraperitoneal drug therapy caused a selective decrease in tumor progression in intraperitoneal NIH: OVCAR5-luc tumors. Conclusions Directly targeting CSC that are a major cause of drug resistant tumor relapse with an anti-CD133 targeted toxin shows promise for ovarian cancer therapy. PMID:23721800

  17. Survivorship Care Planning in Improving Quality of Life in Survivors of Ovarian Cancer

    ClinicalTrials.gov

    2016-08-19

    Cancer Survivor; Stage IA Ovarian Epithelial Cancer; Stage IB Ovarian Epithelial Cancer; Stage IC Ovarian Epithelial Cancer; Stage IIA Ovarian Epithelial Cancer; Stage IIB Ovarian Epithelial Cancer; Stage IIC Ovarian Epithelial Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer

  18. A coumarin derivative (RKS262) inhibits cell-cycle progression, causes pro-apoptotic signaling and cytotoxicity in ovarian cancer cells

    PubMed Central

    Singh, Rakesh K.; Lange, Thilo S.; Kim, Kyu Kwang

    2011-01-01

    Summary Coumarin derivative RKS262 belongs to a new class of potential anti-tumor agents. RKS262 was identified by structural optimization of Nifurtimox which is currently undergoing phase II clinical trials to treat high-risk neuroblastoma. In a NCI60 cell-line assay RKS262 exhibited significant cytotoxicity in ovarian cancer cells and a variety of other cell lines exceeding effects of commercial drugs such as cisplatin, 5-FU, cyclophosphamide or sapacitabine. Various leukemia cell-lines were most sensitive (GI50:~10 nM) while several non-small cell lung cancer cell lines and few cell lines from other tissues were relatively resistant (GI50> *1µM) to RKS262 treatment. The mechanism of cytotoxicity was examined using ovarian cancer cell-line OVCAR-3 as a model. RKS262 treatment resulted in a reduced mitochondria-transmembrane-depolarization potential. RKS262 effects included up-regulation of apoptotic markers and were not correlated with activation of proapoptotic MAP-Kinases (p38, SAP/JNK). RKS262 exerted strong inhibitory effects on oncogene ras, down-regulated DNA-pk KU-80 subunit expression and caused activation of Akt. A signature effect of RKS262 is the regulation of the mitochondrial Bcl2-family pathway. Pro-apoptotic factors Bid, Bad and Bok were up-regulated while expression of pro-survival factors Bcl-xl and Mcl-1 was inhibited. Moreover, at sub-cytotoxic doses RKS262 delayed OVCAR-3 cell-cycle progression through G2 phase and up-regulated p27 while cyclin-D1 and Cdk-6 were down-regulated, indicating that RKS262 is a specific cyclin/CDK inhibitor. In summary, RKS262 has been identified as a molecule belonging to a new class of potential chemotherapeutic agents affecting the viability of multiple cancer cell-lines and causing selective adverse effects on the viability of ovarian cancer cells. PMID:19865799

  19. Targeting a Metalloprotease-PAR1 Signaling System with Cell-Penetrating Pepducins Inhibits Angiogenesis, Ascites, and Progression of Ovarian Cancer

    PubMed Central

    Agarwal, Anika; Covic, Lidija; Sevigny, Leila M; Kaneider, Nicole C; Lazarides, Katherine; Azabdaftari, Gissou; Sharifi, Sheida; Kuliopulos, Athan

    2009-01-01

    Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9 and MMP-1 that culminates in activation of PAR1—a G protein-coupled protease-activated receptor upregulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation and metastasis was effectively inhibited by intraperitoneal administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer. PMID:18790755

  20. Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer.

    PubMed

    Agarwal, Anika; Covic, Lidija; Sevigny, Leila M; Kaneider, Nicole C; Lazarides, Katherine; Azabdaftari, Gissou; Sharifi, Sheida; Kuliopulos, Athan

    2008-09-01

    Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, and MMP-1 that culminates in activation of PAR1, a G protein-coupled protease-activated receptor up-regulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation, and metastasis were effectively inhibited by i.p. administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer. PMID:18790755

  1. Ovarian Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  2. Fe-MIL-101 exhibits selective cytotoxicity and inhibition of angiogenesis in ovarian cancer cells via downregulation of MMP.

    PubMed

    Wang, Jiaqiang; Chen, Daomei; Li, Bin; He, Jiao; Duan, Deliang; Shao, Dandan; Nie, Minfang

    2016-01-01

    Though metal-organic frameworks (MOFs) have inspired potential applications in biomedicine, cytotoxicity studies of MOFs have been relatively rare. Here we demonstrate for the first time that an easily available MOF, Fe-MIL-101, possesses intrinsic activity against human SKOV3 ovarian cancer cells and suppress the proliferation of SKOV3 cells (IC50 = 23.6 μg mL(-1)) and normal mouse embryonic fibroblasts (BABL-3T3, IC50 = 78.3 μg mL(-1)) cells. It was more effective against SKOV3 cells than typical anticancer drugs such as artesunate (ART, IC50 = 96.9 μg mL(-1)) and oxaliplatin (OXA, IC50 = 64.4 μg mL(-1)), but had less effect on normal BABL-3T3 cells compared with ART (IC50 = 36.6 μg mL(-1)) and OXA (IC50 = 13.8 μg mL(-1)). Fe-MIL-101 induced apoptosis of human umbilical vein endothelial cells (HUVECs) via G0/G1 cell cycle arrest and decreased the mitochondrial membrane potential in HUVECs and induced apoptosis. Furthermore, Fe-MIL-101 exhibited stronger antiangiogenic effects in HUVEC cells than antiangiogenic inhibitor (SU5416) via downregulation the expression of MMP-2/9. Our results reveal a new role of Fe-MIL-101 as a novel, non-toxic anti-angiogenic agent that restricted ovarian tumour growth. These findings could open a new avenue of using MOFs as potential therapeutics in angiogenesis-dependent diseases, including ovarian cancer. PMID:27188337

  3. Fe-MIL-101 exhibits selective cytotoxicity and inhibition of angiogenesis in ovarian cancer cells via downregulation of MMP

    PubMed Central

    Wang, Jiaqiang; Chen, Daomei; Li, Bin; He, Jiao; Duan, Deliang; Shao, Dandan; Nie, Minfang

    2016-01-01

    Though metal-organic frameworks (MOFs) have inspired potential applications in biomedicine, cytotoxicity studies of MOFs have been relatively rare. Here we demonstrate for the first time that an easily available MOF, Fe-MIL-101, possesses intrinsic activity against human SKOV3 ovarian cancer cells and suppress the proliferation of SKOV3 cells (IC50 = 23.6 μg mL−1) and normal mouse embryonic fibroblasts (BABL-3T3, IC50 = 78.3 μg mL−1) cells. It was more effective against SKOV3 cells than typical anticancer drugs such as artesunate (ART, IC50 = 96.9 μg mL−1) and oxaliplatin (OXA, IC50 = 64.4 μg mL−1), but had less effect on normal BABL-3T3 cells compared with ART (IC50 = 36.6 μg mL−1) and OXA (IC50 = 13.8 μg mL−1). Fe-MIL-101 induced apoptosis of human umbilical vein endothelial cells (HUVECs) via G0/G1 cell cycle arrest and decreased the mitochondrial membrane potential in HUVECs and induced apoptosis. Furthermore, Fe-MIL-101 exhibited stronger antiangiogenic effects in HUVEC cells than antiangiogenic inhibitor (SU5416) via downregulation the expression of MMP-2/9. Our results reveal a new role of Fe-MIL-101 as a novel, non-toxic anti-angiogenic agent that restricted ovarian tumour growth. These findings could open a new avenue of using MOFs as potential therapeutics in angiogenesis-dependent diseases, including ovarian cancer. PMID:27188337

  4. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

    SciTech Connect

    Xu, Yang; Pang, Xiaoyan; Dong, Mei; Wen, Fang Zhang, Yi

    2013-11-01

    Highlights: •Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. •Nesfatin-1 enhances HO-8910 cell apoptosis. •Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. •The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesity has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.

  5. Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism.

    PubMed

    Ha, T U; Segev, D L; Barbie, D; Masiakos, P T; Tran, T T; Dombkowski, D; Glander, M; Clarke, T R; Lorenzo, H K; Donahoe, P K; Maheswaran, S

    2000-11-24

    Müllerian inhibiting substance (MIS), a transforming growth factor-beta family member, causes regression of the Müllerian duct in male embryos. MIS overexpression in transgenic mice ablates the ovary, and MIS inhibits the growth of ovarian cancer cell lines in vitro, suggesting a key role for this hormone in postnatal development of the ovary. This report describes a mechanism for MIS-mediated growth inhibition in both a human epithelial ovarian cancer cell line and a cell line derived from normal ovarian surface epithelium, which is the origin of human epithelial ovarian cancers. MIS-treated cells accumulated in the G(1) phase of the cell cycle and subsequently underwent apoptosis. MIS up-regulated the cyclin-dependent kinase inhibitor p16 through an MIS type II receptor-mediated mechanism and inhibited growth in the absence of detectable or inactive Rb protein. Prolonged treatment with MIS down-regulated the Rb-related protein p130 and increased the Rb family-regulated transcription factor E2F1, overexpression of which inhibited growth. These findings demonstrate that p16 is required for MIS-mediated growth inhibition in ovarian epithelial cells and tumor cells and suggest that up-regulation of E2F1 also plays a role in this process. PMID:10958795

  6. Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes.

    PubMed

    Nakonechny, Quentin B; Gilks, C Blake

    2016-06-01

    Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are associated with increased risk of developing ovarian carcinoma. Patients with HBOC have a lifetime risk of up to 50% of developing high-grade serous carcinoma of tube or ovary; patients with LS have a 10% lifetime risk of developing endometrioid or clear cell carcinoma of the ovary. Testing all patients with tubo-ovarian high-grade serous carcinoma for mutations associated with HBOC syndrome, and all patients presenting with endometrioid or clear cell carcinoma of the ovary for mutations associated with LS can identify patients with undiagnosed underlying hereditary cancer susceptibility syndromes. PMID:27241103

  7. Inflammatory Breast Cancer from Metastatic Ovarian Cancer

    PubMed Central

    Achariyapota, Vuthinun; Chuangsuwanich, Tuenjai

    2016-01-01

    Metastases to the breast from tumors other than breast carcinomas are extremely rare and represent only 0.2–1.3% of all diagnosed malignant breast tumors. Furthermore, while the most common sites for advanced ovarian cancer metastases are the liver, lung, and pleura, metastasis to the breast from a primary ovarian cancer is uncommon and has only been reported in 0.03–0.6% of all breast cancers. Here we describe a case report of a 50-year-old female patient with a rare case of breast metastases from an advanced ovarian cancer, presenting as inflammatory breast cancer. Our observations emphasize the clinical importance of distinguishing between primary and metastatic breast cancer during diagnosis for the purpose of appropriate prognosis and treatment. PMID:27047697

  8. The human Müllerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4.

    PubMed

    Kersual, Nathalie; Garambois, Véronique; Chardès, Thierry; Pouget, Jean-Pierre; Salhi, Imed; Bascoul-Mollevi, Caroline; Bibeau, Frédéric; Busson, Muriel; Vié, Henri; Clémenceau, Béatrice; Behrens, Christian K; Estupina, Pauline; Pèlegrin, André; Navarro-Teulon, Isabelle

    2014-01-01

    Ovarian cancer has the highest mortality rate among gynecologic malignancies. The monoclonal antibody 12G4 specifically recognizes the human Müllerian inhibiting substance type II receptor (MISRII) that is strongly expressed in human granulosa cell tumors (GCT) and in the majority of human epithelial ovarian cancers (EOC). To determine whether MISRII represents an attractive target for antibody-based tumor therapy, we first confirmed by immunohistochemistry with 12G4 its expression in all tested GCT samples (4/4) and all, but one, EOC human tissue specimens (13/14). We then demonstrated in vitro the internalization of 12G4 in MISRII(high)COV434 cells after binding to MISRII and its ability to increase the apoptosis rate (FACS, DNA fragmentation) in MISRII(high)COV434 (GCT) and MISRII(medium)NIH-OVCAR-3 (EOC) cells that express different levels of MISRII. A standard (51)Cr release assay showed that 12G4 mediates antibody-dependent cell-meditated cytotoxicity. Finally, in vivo assessment of 12G4 anti-tumor effects showed a significant reduction of tumor growth and an increase of the median survival time in mice xenografted with MISRII(high)COV434 or MISRII(medium)NIH-OVCAR-3 cells and treated with 12G4 in comparison to controls treated with an irrelevant antibody. Altogether, our data indicate that MISRII is a new promising target for the control of ovarian GCTs and EOCs. A humanized version of the 12G4 antibody, named 3C23K, is in development for the targeted therapy of MISRII-positive gynecologic cancers. PMID:25517316

  9. 6 Common Cancers - Gynecologic Cancers Cervical, Endometrial, and Ovarian

    MedlinePlus

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Gynecologic Cancers Cervical, Endometrial, and Ovarian Past Issues / Spring 2007 ... of this page please turn Javascript on. Gynecologic Cancers Cervical, Endometrial, and Ovarian NCI estimates that endometrial, ...

  10. Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.

    PubMed

    Musa, Fernanda; Alard, Amandine; David-West, Gizelka; Curtin, John P; Blank, Stephanie V; Schneider, Robert J

    2016-07-01

    There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557-67. ©2016 AACR. PMID:27196780

  11. Molecular imaging in ovarian cancer.

    PubMed

    Reyners, A K L; Broekman, K E; Glaudemans, A W J M; Brouwers, A H; Arts, H J G; van der Zee, A G J; de Vries, E G E; Jalving, M

    2016-04-01

    Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer. PMID:27141066

  12. Profile of olaparib in the treatment of advanced ovarian cancer

    PubMed Central

    Chase, Dana M; Patel, Shreya; Shields, Kristin

    2016-01-01

    Olaparib is a poly(ADP-ribose) polymerase inhibitor that received accelerated approval from the US Food and Drug Administration as monotherapy for patients with germline BRCA mutations and ovarian cancer treated with three or more prior lines of chemotherapy. This article summarizes the mechanism of poly(ADP-ribose) polymerase inhibition, therapeutic profile and uses of olaparib, and current and ongoing literature pertaining to olaparib in advanced ovarian cancer. PMID:27186080

  13. Exercise May Help Thwart Ovarian Cancer

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_159486.html Exercise May Help Thwart Ovarian Cancer Chronic inactivity linked ... TUESDAY, June 21, 2016 (HealthDay News) -- Lack of exercise is associated with an increased risk of ovarian ...

  14. Exercise May Help Thwart Ovarian Cancer

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159486.html Exercise May Help Thwart Ovarian Cancer Chronic inactivity linked ... TUESDAY, June 21, 2016 (HealthDay News) -- Lack of exercise is associated with an increased risk of ovarian ...

  15. Genital Cancers in Women: Ovarian Cancer.

    PubMed

    Kuznia, Angela L; Roett, Michelle A

    2015-11-01

    More than 20,000 US women are diagnosed with ovarian cancer each year. The average lifetime risk is 1.3%, but risk increases with BRCA1 or BRCA2 gene mutations (40% and 18% risk, respectively, by age 70 years) or hereditary nonpolyposis colorectal cancer syndrome (12% lifetime risk). Other risk factors include smoking, possibly past clomiphene use, and more years of ovulation. Symptoms are nonspecific. Abdominal pain is most common; others include pelvic pain, bloating, and early satiety. When ovarian cancer is suspected, evaluation should begin with transvaginal ultrasonography with Doppler studies. Cancer antigen 125 testing can be obtained, but levels are not elevated in all patients. Other biomarkers (eg, OVA1) and scoring systems can be used to help determine if cancer is present. When diagnosed early (stage I), the 5-year survival rate is 90% for epithelial ovarian cancer. However, most patients with epithelial ovarian cancer are diagnosed in stage III or later, with a 5-year survival rate of 17% to 39%. Treatment involves total abdominal hysterectomy and bilateral salpingo-oophorectomy, with or without chemotherapy. Fertility-preserving options can be considered in some early-stage cancers, followed by more definitive surgical procedures. There is no evidence that routine screening is beneficial and it is associated with significant harms from unnecessary procedures. Women with genetic syndromes that increase risk should be considered for prophylactic bilateral salpingo-oophorectomy. PMID:26569048

  16. Ovarian stimulation in cancer patients.

    PubMed

    Cakmak, Hakan; Rosen, Mitchell P

    2013-05-01

    The patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo cryopreservation requires an individualized assessment. This review highlights the new protocols that are emerging to reduce time constraints and emphasizes management considerations to decrease complications. PMID:23635348

  17. [Epidemiologic factors in ovarian cancer].

    PubMed

    Curie, P; Sussmann, M; Treisser, A; Renaud, R

    1985-05-01

    Ovarian carcinoma is the most severe gynecological cancer with an overall incidence of 12 per 1000 Americans or Europeans developing it over 40 years of age. Only 3 of the 12 cases will receive efficient care because the diagnosis will be made too late. This study reveals the principal risk factors i.e. upper socioeconomic echelon, ovarian function uninterrupted by a pregnancy or usage of oral contraceptives, anamnestic evidence of ovarian carcinoma in the family, some hereditary disorders, external insults (talcum powder). The synthesis of these various risk factors permits a comprehensive review of the hypotheses of pathogenesis concerning recurrence of tumors. But corollary epidemiologic studies are still needed to try to define better the high risk groups whose follow-up systematic detection and testing is a priority. PMID:4023542

  18. Knockdown of CRM1 inhibits the nuclear export of p27(Kip1) phosphorylated at serine 10 and plays a role in the pathogenesis of epithelial ovarian cancer.

    PubMed

    Wang, You; Wang, Yingying; Xiang, Jingying; Ji, Fang; Deng, Yan; Tang, Chunhui; Yang, Shuyun; Xi, Qinghua; Liu, Rong; Di, Wen

    2014-02-01

    In a previous study, the nuclear export protein chromosomal region maintenance (CRM1) was correlated with p27(Kip1) in glioma. The aims of the present study were to investigate the expression of CRM1 and pSer10p27 and their functional roles in epithelial ovarian cancer (EOC) tissues. Using immunohistochemical analysis, CRM1 and pSer10p27 expression levels were shown to be associated with histologic stage and grade (P<0.05). High CRM1 and pSer10p27 expression levels were prognostic indicators of overall survival (P<0.05). Knockdown of CRM1 and pSer10p27 expression arrested cell cycle progression and inhibited the proliferation of SKOV3 cells both in vitro and in vivo. These data support the idea that pSer10p27 and CRM1 play cooperative roles in EOC. PMID:24018641

  19. Ovarian metastasis from colorectal cancer.

    PubMed

    Birnkrant, A; Sampson, J; Sugarbaker, P H

    1986-11-01

    Controversies exist regarding the surgical treatment of the ovaries in women with primary colorectal cancer. A review of the authors' experience and the surgical literature reveals an incidence of ovarian metastases from colorectal cancer of approximately 6 percent. This problem may occur somewhat more frequently in premenopausal women. Resection of the ovaries at the time of colectomy is unlikely to affect survival. Removal of the ovaries at the time of bowel resection will prevent repeat laparotomy to resect an ovarian mass in approximately 2 percent of women with large bowel cancer. Oophorectomy should be performed in all postmenopausal females at the time of primary resection. Oophorectomy should be performed in premenopausal women if any gross abnormality of the ovary is detected or if peritoneal implants are seen at the time of primary resection. PMID:3533472

  20. Antivascular Therapy for Epithelial Ovarian Cancer

    PubMed Central

    Duhoux, Francois P.; Machiels, Jean-Pascal

    2010-01-01

    Ovarian cancer is the fifth largest cancer killer in women. Improved understanding of the molecular pathways implicated in the pathogenesis of ovarian cancer has led to the investigation of novel targeted therapies. Ovarian cancer is characterized by an imbalance between pro- and antiangiogenic factors in favor of angiogenesis activation. Various antivascular strategies are currently under investigation in ovarian cancer. They can schematically be divided into antiangiogenic and vascular-disrupting therapies. This paper provides a comprehensive review of these new treatments targeting the tumor vasculature in this disease. Promising activities have been detected in phase II trials, and results of phase III clinical trials are awaited eagerly. PMID:20072701

  1. Belinostat and Carboplatin in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Carboplatin or Cisplatin

    ClinicalTrials.gov

    2014-06-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer

  2. Ovulation and extra-ovarian origin of ovarian cancer.

    PubMed

    Yang-Hartwich, Yang; Gurrea-Soteras, Marta; Sumi, Natalia; Joo, Won Duk; Holmberg, Jennie C; Craveiro, Vinicius; Alvero, Ayesha B; Mor, Gil

    2014-01-01

    The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies. PMID:25135607

  3. Early Preinvasive Lesions in Ovarian Cancer

    PubMed Central

    Chene, Gautier; Lamblin, Gery; Le Bail-Carval, Karine; Chabert, Philippe; Bakrin, Naoual; Mellier, Georges

    2014-01-01

    Faced with the catastrophic prognosis for ovarian cancer due to the fact that it is most often diagnosed late at the peritoneal carcinomatosis stage, screening and early detection could probably reduce the mortality rate. A better understanding of the molecular characteristics of the different ovarian cancer subtypes and their specific molecular signatures is indispensable prior to development of new screening strategies. We discuss here the early natural history of ovarian cancer and its origins. PMID:24804229

  4. Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

    ClinicalTrials.gov

    2014-12-18

    Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

  5. δ-Cadinene inhibits the growth of ovarian cancer cells via caspase-dependent apoptosis and cell cycle arrest

    PubMed Central

    Hui, Li-Mei; Zhao, Guo-Dong; Zhao, Jian-Jun

    2015-01-01

    Ovarian cancer is one of the most common causes of mortality among all cancers in females and is the primary cause of mortality from gynecological malignancies. The objective of the current research work was to evaluate a naturally occurring sesquiterpene-δ-Cadinene for its antiproliferative and apoptotic effects on human ovary cancer (OVCAR-3) cells. We also demonstrated the effect of δ-Cadinene on cell cycle phase distribution, intracellular damage and caspase activation. Sulforhodamine B (SRB) assay was used to evaluate the antiproliferative effect of δ-cadinene on OVCAR-3 cells. Cellular morphology after δ-cadinene treatment was demonstrated by inverted phase contrast microscopy, fluorescence microscopy and transmission electron microscopy. Flow cytometry was used to analyze the effect of δ-cadinene on cell cycle phase distribution and apoptosis using propidium iodide and Annexin V-fluorescein isothiocyanate (FITC)/PI kit. The results revealed that δ-cadinene induced dose-dependent as well as time-dependent growth inhibitory effects on OVACR-3 cell line. δ-cadinene also induced cell shrinkage, chromatin condensation and nuclear membrane rupture which are characteristic of apoptosis. Treatment with different doses of δ-cadinene also led to cell cycle arrest in sub-G1 phase which showed dose-dependence. Western blotting assay revealed that δ-cadinene led to activation of caspases in OVCAR-3 cancer cells. PARP cleavage was noticed at 50 µM dose of δ-cadinene with the advent of the cleaved 85-kDa fragment after exposure to δ-cadinene. At 100 µM, only the cleaved form of PARP was detectable. Pro-caspase-8 expression remained unaltered until 10 µM dose of δ-cadinene. However, at 50 and 100 µM dose, pro-caspase-8 expression was no longer detectable. There was a significant increase in the caspase-9 expression levels after 50 and 100 µM δ-cadinene treatments. PMID:26261482

  6. Surgical management of recurrent ovarian cancer.

    PubMed

    Leitao, Mario M; Chi, Dennis S

    2009-04-01

    Surgery is the cornerstone of treatment for patients with advanced ovarian cancer. The majority of patients with advanced ovarian cancer who experience a clinical remission after initial surgery will develop a recurrence. The optimal management for patients with recurrent ovarian cancer remains to be defined. Chemotherapy is frequently used with varying response rates. Repeat surgical cytoreduction appears to offer a survival benefit for select patients with recurrent ovarian cancer and should be considered. Surgery also plays a role in the palliation of certain patients. Continued investigations, especially randomized trials, are needed to further define the optimal treatment modalities for these patients. PMID:19332245

  7. Belinostat in Treating Patients With Advanced Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer or Ovarian Low Malignant Potential Tumors

    ClinicalTrials.gov

    2013-04-11

    Fallopian Tube Cancer; Primary Peritoneal Cavity Cancer; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Ovarian Epithelial Cancer; Stage III Borderline Ovarian Surface Epithelial-stromal Tumor; Stage III Ovarian Epithelial Cancer; Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor; Stage IV Ovarian Epithelial Cancer

  8. Downregulation of BC200 in ovarian cancer contributes to cancer cell proliferation and chemoresistance to carboplatin

    PubMed Central

    WU, DI; WANG, TIANZHEN; REN, CHENGCHENG; LIU, LEI; KONG, DAN; JIN, XIAOMING; LI, XIAOBO; ZHANG, GUANGMEI

    2016-01-01

    Previous studies have demonstrated that long non-coding RNAs (lncRNAs) serve an important role in carcinogenesis. BC200 is a lncRNA that is reportedly associated with ovarian cancer. The aim of the present study was to investigate this potential association between BC200 and ovarian cancer, and to subsequently analyze the biological function of BC200 in the disease. BC200 expression was compared in ovarian cancer tissue and normal ovarian tissue samples through the use of quantitative polymerase chain reaction. To allow the biological function of BC200 in ovarian cancer to be analyzed, small interfering RNA was used to knock down the expression of BC200 in SKOV3 and A2780 ovarian cancer cells. The proliferative, invasive and migratory abilities of the cells were identified by means of cell counting kits and Transwell assays. Carboplatin was also used to treat the ovarian cancer cells, and a luminescent cell viability assay was subsequently used to detect the sensitivity of the cells to the carboplatin. The results demonstrated that BC200 expression was reduced in ovarian cancer compared with normal ovarian tissue samples. In the SKOV3 and A2780 cells, BC200 exerted no effect on invasive or migratory ability, however, the inhibition of BC200 was demonstrated to promote cell proliferation. Additionally, it was observed that carboplatin induced BC200 expression in the cell lines, and that the inhibition of BC200 decreased the sensitivity of the cells to the drug. BC200 is therefore likely to have a tumor suppressive function in ovarian cancer by affecting cell proliferation. Furthermore, BC200 appears to serve a role in the mediation of carboplatin-induced ovarian cancer cell death. PMID:26893717

  9. Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth.

    PubMed

    Huang, Jie; Hu, Wei; Hu, Limin; Previs, Rebecca A; Dalton, Heather J; Yang, Xiao-Yun; Sun, Yunjie; McGuire, Michael; Rupaimoole, Rajesha; Nagaraja, Archana S; Kang, Yu; Liu, Tao; Nick, Alpa M; Jennings, Nicholas B; Coleman, Robert L; Jaffe, Robert B; Sood, Anil K

    2016-06-01

    Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344-52. ©2016 AACR. PMID:27009216

  10. Hemiasterlin derivative (R)(S)(S)-BF65 and Akt inhibitor MK-2206 synergistically inhibit SKOV3 ovarian cancer cell growth.

    PubMed

    Lai, Wei-Ting; Cheng, Kai-Lin; Baruchello, Riccardo; Rondanin, Riccardo; Marchetti, Paolo; Simoni, Daniele; Lee, Ray M; Guh, Jih-Hwa; Hsu, Lih-Ching

    2016-08-01

    We reported previously that a hemiasterlin derivative BF65 is a potent anticancer agent that can inhibit microtubule assembly. Here we show that a more potent stereospecific diastereomer (R)(S)(S)-BF65 can synergize with an allosteric Akt inhibitor MK-2206 to suppress the growth of SKOV3 ovarian cancer cells with constitutively active Akt. (R)(S)(S)-BF65 induced mitotic arrest and MK-2206 caused G0/G1 arrest, while the combination of both induced simultaneous G0/G1 and G2/M cell cycle arrest. (R)(S)(S)-BF65 induced phosphorylation and inactivation of Bcl-2, and downregulated Mcl-1, consequently may lead to apoptosis. (R)(S)(S)-BF65 inhibited mitogen-activated protein kinases (MAPKs), which may stimulate cell proliferation upon activation. (R)(S)(S)-BF65 also induced DNA damage after long-term treatment. MK-2206 is known to inhibit phosphorylation and activation of Akt and suppress cancer cell growth. The combination of (R)(S)(S)-BF65 and MK-2206 also inhibited the Akt pathway. Interestingly, MK-2206 upregulated Bcl-2 and induced activation of MAPKs in SKOV3 cells; however, when combined with (R)(S)(S)-BF65, these prosurvival effects were reversed. The combination also more significantly decreased Mcl-1 protein, increased PARP cleavage, and induced γ-H2AX, a DNA damage marker. Remarkably, MK-2206 enhanced the microtubule depolymerization effect of (R)(S)(S)-BF65. The combination of (R)(S)(S)-BF65 and MK-2206 also markedly inhibited cell migration. Thus, MK-2206 synergizes with (R)(S)(S)-BF65 to inhibit SKOV3 cell growth via downregulating the Akt signaling pathway, and enhancing the microtubule disruption effect of (R)(S)(S)-BF65. (R)(S)(S)-BF65 in turn suppresses Bcl-2 and MAPKs induced by MK-2206. (R)(S)(S)-BF65 and MK-2206 compensate each other leading to increased apoptosis and enhanced cytotoxicity, and may also suppress cancer cell invasion. PMID:27328368

  11. OVARIAN CANCER: INVOLVEMENT OF THE MATRIX METALLOPROTEINASES

    PubMed Central

    Al-Alem, Linah; Curry, Thomas E.

    2016-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancies. Reasons for the high mortality rate associated with ovarian cancer include a late diagnosis at which time the cancer has metastasized throughout the peritoneal cavity. Cancer metastasis is facilitated by the remodeling of the extracellular tumor matrix by a family of proteolytic enzymes known as the matrix metalloproteinases (MMPs). There are 23 members in the MMP family, many of which have been reported to be associated with ovarian cancer. In the current paradigm, ovarian tumor cells and the surrounding stromal cells stimulate the synthesis and/or activation of various MMPs to aid in tumor growth, invasion, and eventual metastasis. This review sheds light on the different MMPs in the various types of ovarian cancer and their impact on the progression of this gynecologic malignancy. PMID:25918438

  12. Targeted Therapies in Epithelial Ovarian Cancer

    PubMed Central

    Dean, Emma; El-Helw, Loaie; Hasan, Jurjees

    2010-01-01

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer. PMID:24281034

  13. TRPM7 is required for ovarian cancer cell growth, migration and invasion

    SciTech Connect

    Wang, Jing; Liao, Qian-jin; Zhang, Yi; Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng; Zhang, Qiong-yu; Xiao, Ling

    2014-11-28

    Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

  14. Rethinking Ovarian Cancer: Recommendations for Improving Outcomes

    PubMed Central

    Vaughan, Sebastian; Coward, Jermaine I.; Bast Jr., Robert C.; Berchuck, Andy; Berek, Jonathan S.; Brenton, James D.; Coukos, George; Crum, Christopher C.; Drapkin, Ronny; Etemadmoghadam, Dariush; Friedlander, Michael; Gabra, Hani; Kaye, Stan B.; Lord, Chris J.; Lengyel, Ernst; Levine, Douglas A.; McNeish, Iain A.; Menon, Usha; Mills, Gordon B.; Nephew, Kenneth P.; Oza, Amit M.; Sood, Anil K.; Stronach, Euan A.; Walczak, Henning; Bowtell, David D.; Balkwill, Frances R.

    2012-01-01

    There have been major advances in our understanding of the cellular and molecular biology of the human malignancies collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Perspective. PMID:21941283

  15. Effects of Per2 overexpression on growth inhibition and metastasis, and on MTA1, nm23-H1 and the autophagy-associated PI3K/PKB signaling pathway in nude mice xenograft models of ovarian cancer

    PubMed Central

    WANG, ZHAOXIA; LI, LI; WANG, YANG

    2016-01-01

    K/PKB, were significantly downregulated, when compared with the PBS control and empty plasmid groups (P<0.001). Thus, it was demonstrated that Per2 is closely associated with the development of ovarian cancer, and late-stage ovarian cancer is associated with Per2 mutation or deletion. Per2 overexpression, via exogenous infusion reduced the ovarian cancer growth rate, which was demonstrated by a significant increase in the tumor inhibition rate. In addition, Per2 may inhibit the expression of MTA-1 and promote the expression of nm23-H1 to restrict ovarian tumor growth and metastasis. Finally, it is hypothesized that Per2 affects autophagy by interfering with the PI3K/PKB signaling pathway, causing inhibition of tumor angiogenesis in order to inhibit tumor growth. PMID:27082164

  16. Effects of Per2 overexpression on growth inhibition and metastasis, and on MTA1, nm23-H1 and the autophagy-associated PI3K/PKB signaling pathway in nude mice xenograft models of ovarian cancer.

    PubMed

    Wang, Zhaoxia; Li, Li; Wang, Yang

    2016-06-01

    associated signaling pathway PI3K/PKB, were significantly downregulated, when compared with the PBS control and empty plasmid groups (P<0.001). Thus, it was demonstrated that Per2 is closely associated with the development of ovarian cancer, and late‑stage ovarian cancer is associated with Per2 mutation or deletion. Per2 overexpression, via exogenous infusion reduced the ovarian cancer growth rate, which was demonstrated by a significant increase in the tumor inhibition rate. In addition, Per2 may inhibit the expression of MTA‑1 and promote the expression of nm23‑H1 to restrict ovarian tumor growth and metastasis. Finally, it is hypothesized that Per2 affects autophagy by interfering with the PI3K/PKB signaling pathway, causing inhibition of tumor angiogenesis in order to inhibit tumor growth. PMID:27082164

  17. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol®-resistant ovarian cancer

    PubMed Central

    Shen, Yao-An; Li, Wai-Hou; Chen, Po-Hung; He, Chun-Lin; Chang, Yen-Hou; Chuang, Chi-Mu

    2015-01-01

    Taxol® remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming. In this work, we aimed to investigate the impacts of a novel liposome-encapsulated paclitaxel (Nano-Taxol) on the stemness phenotype and metabolic reprogramming. A paclitaxel-resistant cell line (TR) was established at first. Tumor growth was induced in the mice peritoneal cavity by inoculation of TR cells. A 2x2 factorial experiment was designed to test the therapeutic efficacy in which factor 1 represented the comparison of drugs (Taxol® versus Nano-Taxol), while factor 2 represented the delivery route (intravenous versus intraperitoneal delivery). In this work, we found that intraperitoneal delivery of Nano-Taxol redirects metabolic reprogramming, from glycolysis to oxidative phosphorylation, and effectively suppresses cancer stem cells. Also, intraperitoneal delivery of Nano-Taxol led to a significantly better control of tumor growth compared with intravenous delivery of Taxol® (current standard treatment). This translational research may serve as a novel pathway for the drug development of nanomedicine. In the future, this treatment modality may be extended to treat several relevant cancers that have been proved to be suitable for the loco-regional delivery of therapeutic agents, including colon cancer, gastric cancer, and pancreatic cancer. PMID:26175846

  18. Ovarian cancer mortality and industrial pollution.

    PubMed

    García-Pérez, Javier; Lope, Virginia; López-Abente, Gonzalo; González-Sánchez, Mario; Fernández-Navarro, Pablo

    2015-10-01

    We investigated whether there might be excess ovarian cancer mortality among women residing near Spanish industries, according to different categories of industrial groups and toxic substances. An ecologic study was designed to examine ovarian cancer mortality at a municipal level (period 1997-2006). Population exposure to pollution was estimated by means of distance from town to facility. Using Poisson regression models, we assessed the relative risk of dying from ovarian cancer in zones around installations, and analyzed the effect of industrial groups and pollutant substances. Excess ovarian cancer mortality was detected in the vicinity of all sectors combined, and, principally, near refineries, fertilizers plants, glass production, paper production, food/beverage sector, waste treatment plants, pharmaceutical industry and ceramic. Insofar as substances were concerned, statistically significant associations were observed for installations releasing metals and polycyclic aromatic chemicals. These results support that residing near industries could be a risk factor for ovarian cancer mortality. PMID:26046426

  19. Role of PAR-4 in ovarian cancer.

    PubMed

    Meynier, Sonia; Kramer, Marianne; Ribaux, Pascale; Tille, Jean-Christophe; Delie, Florence; Petignat, Patrick; Cohen, Marie

    2015-09-01

    Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis. PMID:26246468

  20. Role of PAR-4 in ovarian cancer

    PubMed Central

    Meynier, Sonia; Kramer, Marianne; Ribaux, Pascale; Tille, Jean-Christophe; Delie, Florence; Petignat, Patrick; Cohen, Marie

    2015-01-01

    Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis. PMID:26246468

  1. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    SciTech Connect

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja; Kulcenty, Katarzyna; Wierzchowski, Marcin; Kaczmarek, Mariusz; Murias, Marek; Kwiatkowska-Borowczyk, Eliza; Jodynis-Liebert, Jadwiga

    2012-08-15

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC{sub 50} = 0.71 μM) and SKOV-3 (IC{sub 50} = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  2. EGEN-001 and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2014-08-11

    Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer

  3. What Should You Ask Your Doctor about Ovarian Cancer?

    MedlinePlus

    ... cancer? What should you ask your doctor about ovarian cancer? It is important for you to have honest, ... are some questions to consider: What type of ovarian cancer do I have? Has my cancer spread beyond ...

  4. Targeting c-MYC in Platinum-Resistant Ovarian Cancer.

    PubMed

    Reyes-González, Jeyshka M; Armaiz-Peña, Guillermo N; Mangala, Lingegowda S; Valiyeva, Fatma; Ivan, Cristina; Pradeep, Sunila; Echevarría-Vargas, Ileabett M; Rivera-Reyes, Adrian; Sood, Anil K; Vivas-Mejía, Pablo E

    2015-10-01

    The purpose of this study was to investigate the molecular and therapeutic effects of siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient's data extracted from The Cancer Genome Atlas (TCGA) portal showed that the disease-free (DFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared with their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell-cycle progression, and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer cells. Significant inhibition of cell growth and viability, cell-cycle arrest, and activation of apoptosis were observed upon siRNA-mediated c-MYC depletion. In addition, single weekly doses of c-MYC-siRNA incorporated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000)-based nanoliposomes resulted in significant reduction in tumor growth. These findings identify c-MYC as a potential therapeutic target for ovarian cancers expressing high levels of this oncoprotein. PMID:26227489

  5. Therapeutic advances in ovarian cancer.

    PubMed

    Rader, J S

    1992-02-01

    The propensity of ovarian cancer to recur--even after initial chemotherapeutic responses--is a problem that has been given a great deal of attention during the past year in the literature dealing with the treatment of ovarian cancer. Most of the articles address techniques to improve the percent of initial and secondary treatment responses. Several studies have described cytoreductive techniques to decrease the remaining tumor size for improved chemotherapeutic response. Cross-resistance between platinum analogues has been reconfirmed. However, improved secondary responses were seen when repeat treatment with platinum agents were preceded by a longer interval from initial platinum agent therapy. Radiation therapy has been shown to offer little solution to recurrent disease except possibly in a select group of patients with microscopic disease at second-look laparotomy. Reports on the use of carboplatin continue to demonstrate good initial responses, with decreased toxicity compared with cisplatin. Granisetron has been shown to significantly decrease the nausea and vomiting caused by emetogenic chemotherapy like cisplatin. PMID:1543823

  6. Metformin Hydrochloride, Carboplatin, and Paclitaxel in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-05-01

    Ovarian Papillary Serous Carcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer

  7. Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-07-05

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  8. OPT-821 With or Without Vaccine Therapy in Treating Patients With Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Peritoneal Cancer in Second or Third Complete Remission

    ClinicalTrials.gov

    2016-03-16

    Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  9. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.

    PubMed

    Bowtell, David D; Böhm, Steffen; Ahmed, Ahmed A; Aspuria, Paul-Joseph; Bast, Robert C; Beral, Valerie; Berek, Jonathan S; Birrer, Michael J; Blagden, Sarah; Bookman, Michael A; Brenton, James D; Chiappinelli, Katherine B; Martins, Filipe Correia; Coukos, George; Drapkin, Ronny; Edmondson, Richard; Fotopoulou, Christina; Gabra, Hani; Galon, Jérôme; Gourley, Charlie; Heong, Valerie; Huntsman, David G; Iwanicki, Marcin; Karlan, Beth Y; Kaye, Allyson; Lengyel, Ernst; Levine, Douglas A; Lu, Karen H; McNeish, Iain A; Menon, Usha; Narod, Steven A; Nelson, Brad H; Nephew, Kenneth P; Pharoah, Paul; Powell, Daniel J; Ramos, Pilar; Romero, Iris L; Scott, Clare L; Sood, Anil K; Stronach, Euan A; Balkwill, Frances R

    2015-11-01

    High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID:26493647

  10. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

    PubMed Central

    Bowtell, David D.; Böhm, Steffen; Ahmed, Ahmed A.; Aspuria, Paul-Joseph; Bast, Robert C.; Beral, Valerie; Berek, Jonathan S.; Birrer, Michael J.; Blagden, Sarah; Bookman, Michael A.; Brenton, James; Chiappinelli, Katherine B.; Martins, Filipe Correia; Coukos, George; Drapkin, Ronny; Edmondson, Richard; Fotopoulou, Christina; Gabra, Hani; Galon, Jérôme; Gourley, Charlie; Heong, Valerie; Huntsman, David G.; Iwanicki, Marcin; Karlan, Beth Y.; Kaye, Allyson; Lengyel, Ernst; Levine, Douglas A.; Lu, Karen H.; McNeish, Iain A.; Menon, Usha; Narod, Steve A.; Nelson, Brad H.; Nephew, Kenneth P.; Pharoah, Paul; Powell, Daniel J.; Ramos, Pilar; Romero, Iris L.; Scott, Clare L.; Sood, Anil K.; Stronach, Euan A.; Balkwill, Frances R.

    2016-01-01

    High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This ‘roadmap’ for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID:26493647

  11. Epidemiological characteristics of ovarian cancer in Korea

    PubMed Central

    Park, Boyoung; Park, Sohee; Kim, Tae-Joong; Ma, Seung Hyun; Kim, Byoung-Gie; Kim, Yong-Man; Kim, Jae Weon; Kang, Sokbom; Kim, Jaehoon; Kim, Tae Jin; Yoo, Keun-Young

    2010-01-01

    Objective This study was conducted to examine recent trends in ovarian cancer incidence and mortality and secular trends in demographic factors in Korea. Methods With the data from Korea Central Cancer Registry, International Agency for Research on Cancer, Korean Death Registry, and World Health Organization's Statistical Information System, we calculated age-standardized incidence and mortality rates for ovarian cancer. Also we estimated future incidence of ovarian and cervical cancer using linear regression model. To assess the demographic trend, data from national surveys in Korea or results from published papers were searched. Results Ovarian cancer incidence rate was similar to that in women worldwide but lower than those in Western countries, and the trend has been increased steadily. Ovarian cancer-related mortality rates have been increasing in Korea, even though those in western and some Asian countries, such as China, have been decreasing. Age-specific incidence rate and mortality rate showed steep increases with advancing age. The incidence rate of ovarian cancer was estimated to surpass that of uterine cervix cancer in 2015. Korea showed rapid changes in nutritional, reproductive, and anthropometric factors. Conclusion These recent trends in ovarian cancer incidence and mortality may be partly attributed to gradual westernizing of life styles and to changes in socio-demographic behavior factors. In particular, the increasing trend in ovarian cancer mortality in Korea may be attributed to a real rise in mortality as well as, in part, a decline in misclassification bias related to an increase in the proportion of deaths confirmed by physician diagnosis. PMID:21278886

  12. Ovarian cancer: emerging molecular-targeted therapies

    PubMed Central

    Sourbier, Carole

    2012-01-01

    With about 22,000 new cases estimated in 2012 in the US and 15,500 related deaths, ovarian cancer is a heterogeneous and aggressive disease. Even though most of patients are sensitive to chemotherapy treatment following surgery, recurring disease is almost always lethal, and only about 30% of the women affected will be cured. Thanks to a better understanding of the molecular mechanisms underlying ovarian cancer malignancy, new therapeutic options with molecular-targeted agents have become available. This review discusses the rationale behind molecular-targeted therapies and examines how newly identified molecular targets may enhance personalized therapies for ovarian cancer patients. PMID:22807625

  13. Olaparib for the treatment of ovarian cancer.

    PubMed

    Bornstein, E; Jimeno, A

    2016-01-01

    Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, is the first FDA-approved drug in its class for patients with ovarian cancer, specifically in a subset of patients with BRCA mutations and prior chemotherapy treatments. PARP inhibitors have had other implications in different solid tumor types including breast, gastric and pancreatic malignancies. In light of the recent FDA approval of olaparib for the treatment of ovarian cancer, this article aims to outline the mechanisms and implications of the drug. With a favorable adverse event profile and improved outcomes, including progression-free survival, olaparib has demonstrated augmentation to therapeutic options in the treatment of ovarian cancer. PMID:26937492

  14. Genomic similarities between breast and ovarian cancers

    Cancer.gov

    One subtype of breast cancer shares many genetic features with high-grade serous ovarian cancer, a cancer that is very difficult to treat, according to researchers supported by the National Institutes of Health. The findings suggest that the two cancers a

  15. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression.

    PubMed

    Nordin, Noraziah; Majid, Nazia Abdul; Hashim, Najihah Mohd; Rahman, Mashitoh Abd; Hassan, Zalila; Ali, Hapipah Mohd

    2015-01-01

    Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression

  16. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression

    PubMed Central

    Nordin, Noraziah; Majid, Nazia Abdul; Hashim, Najihah Mohd; Rahman, Mashitoh Abd; Hassan, Zalila; Ali, Hapipah Mohd

    2015-01-01

    Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression

  17. Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

    PubMed Central

    XIAO, JUAN; XU, MANMAN; HOU, TENG; HUANG, YONGWEN; YANG, CHENLU; LI, JUNDONG

    2015-01-01

    Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho-Src-Y416 (p-Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V-fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p-Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p-Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti-ovarian cancer properties, by downregulating p-Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25–0.93 and 0.31–0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti-ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian

  18. HOXB13 promotes ovarian cancer progression

    PubMed Central

    Miao, Jiangyong; Wang, Zuncai; Provencher, Heather; Muir, Beth; Dahiya, Sonika; Carney, Erin; Leong, Chee-Onn; Sgroi, Dennis C.; Orsulic, Sandra

    2007-01-01

    Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53−/− mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer. PMID:17942676

  19. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-01-01

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration. PMID:27271583

  20. General Information about Ovarian Epithelial Cancer

    MedlinePlus

    ... Primary Peritoneal Cancer Treatment (PDQ®)–Patient Version General Information About Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  1. Genetic and molecular changes in ovarian cancer

    PubMed Central

    Hollis, Robert L; Gourley, Charlie

    2016-01-01

    Epithelial ovarian cancer represents the most lethal gynecological malignancy in the developed world, and can be divided into five main histological subtypes: high grade serous, endometrioid, clear cell, mucinous and low grade serous. These subtypes represent distinct disease entities, both clinically and at the molecular level. Molecular analysis has revealed significant genetic heterogeneity in ovarian cancer, particularly within the high grade serous subtype. As such, this subtype has been the focus of much research effort to date, revealing molecular subgroups at both the genomic and transcriptomic level that have clinical implications. However, stratification of ovarian cancer patients based on the underlying biology of their disease remains in its infancy. Here, we summarize the molecular changes that characterize the five main ovarian cancer subtypes, highlight potential opportunities for targeted therapeutic intervention and outline priorities for future research. PMID:27458531

  2. Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro.

    PubMed

    Wang, Wen-Jing; Sui, Hua; Qi, Cong; Li, Qi; Zhang, Jie; Wu, Shao-Fei; Mei, Ming-Zhu; Lu, Ying-Yu; Wan, Yi-Ting; Chang, Hannah; Guo, Piao-Ting

    2016-07-01

    Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1α (HIF-1α) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1α and ABCG2 was tested using quantitative PCR, western blotting, and immuno-fluorescence under different culture conditions and treated with UA. Knockdown of HIF-1α by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1α under different culture conditions. HIF-1α inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1α and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1α and ABCG2. PMID:27221674

  3. Cytogenetic studies in ovarian cancer.

    PubMed

    Whang-Peng, J; Knutsen, T; Douglass, E C; Chu, E; Ozols, R F; Hogan, W M; Young, R C

    1984-01-01

    Cytogenetic studies of ovarian cancer have been conducted in the Medicine Branch, NCI, National Institutes of Health for 5 years. A total of 72 patients were studied by direct preparation and/or 1- to 3-day short-term culture of ascites (86 samples), pleural fluid (4 samples), and tumor (2 samples). Repeat examinations (1-24 months later) were performed in 7 of the 72 patients. Forty-four patients (62%) were successfully analyzed with banding techniques: 6 patients had adenocarcinoma, 7 had serous adenocarcinoma, 13 had serous papillary adenocarcinoma, 7 had serous papillary cystadenocarcinoma, 2 had mucinous adenocarcinoma, 6 had undifferentiated or poorly differentiated adenocarcinoma, 1 had clear cell adenocarcinoma, and 2 were not classified. Of these 44 patients, 29 had received prior chemotherapy, 14 were untreated, and in 1 patient the treatment status was unknown. Aneuploidy was observed in all patients and there was considerable variation in the chromosome numbers (even within single samples), often ranging from diploidy to triploidy to tetraploidy. All 44 patients had numerical abnormalities and 39 had structural abnormalities. The chromosomes most frequently involved in structural abnormalities (in decreasing order according to the number of patients involved) were #1, #3, #2, #4, #9, #10, #15, #19, #6, and #11; the least involved chromosomes were #21 and #5. Clone formation and the number of chromosomes involved in structural abnormalities increased with duration of disease and were more extensive in patients treated with chemotherapy than in patients treated with surgery alone. Our data did not show a deletion of chromosome #6 (6q-) to be specific for ovarian cancer. PMID:6690026

  4. Surgical management of epithelial ovarian cancer.

    PubMed

    Salani, Ritu; Bristow, Robert E

    2012-03-01

    Ovarian cancer affects approximately 21,880 women and accounts for over 13,000 deaths annually in the United States. Although survival rates have improved over the past several decades, directly as a result of advances in chemotherapy and surgery, ovarian cancer continues to have high mortality rates. Understanding the multiple roles of surgery throughout the disease course is the focus of this review. PMID:22343231

  5. Rethinking ovarian cancer: recommendations for improving outcomes.

    PubMed

    Vaughan, Sebastian; Coward, Jermaine I; Bast, Robert C; Berchuck, Andy; Berek, Jonathan S; Brenton, James D; Coukos, George; Crum, Christopher C; Drapkin, Ronny; Etemadmoghadam, Dariush; Friedlander, Michael; Gabra, Hani; Kaye, Stan B; Lord, Chris J; Lengyel, Ernst; Levine, Douglas A; McNeish, Iain A; Menon, Usha; Mills, Gordon B; Nephew, Kenneth P; Oza, Amit M; Sood, Anil K; Stronach, Euan A; Walczak, Henning; Bowtell, David D; Balkwill, Frances R

    2011-10-01

    There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article. PMID:21941283

  6. The treatment of early stage ovarian cancer.

    PubMed

    Young, R C

    1995-10-01

    Approximately one third of women with ovarian cancer present with localized disease. A series of recent studies have identified a population of patients who require only comprehensive surgical staging for optimal results and another group that may benefit from adjuvant therapy. A series of national and international studies are evaluating a variety of adjuvant treatments in prospective randomized trials that may enhance long-term survival in poor-prognosis early ovarian cancer. PMID:7481865

  7. [The molecular biology of epithelial ovarian cancer].

    PubMed

    Leary, Alexandra; Pautier, Patricia; Tazi, Youssef; Morice, Philippe; Duvillard, Pierre; Gouy, Sébastien; Uzan, Catherine; Gauthier, Hélène; Balleyguier, Corinne; Lhommé, Catherine

    2012-12-01

    Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research. PMID:23238064

  8. Pharmacoprevention for hereditary breast and ovarian cancer.

    PubMed

    Cazzaniga, Massimiliano; Bonanni, Bernardo

    2016-10-01

    Hereditary breast and ovarian cancer (HBOC) syndrome is an important women's health condition characterized by an increased susceptibility to the development of cancer, in particular breast and ovarian neoplasms, and is caused by an inherited germline genetic mutation in one or both tumor suppressor genes named BRCA1 and BRCA2. This monographic issue provides an update on our knowledge of this syndrome with particular emphasis on the risk reduction strategies through a pharmacopreventive approach. PMID:26928419

  9. Dietary energy balance modulates ovarian cancer progression and metastasis

    PubMed Central

    Al-Wahab, Zaid; Tebbe, Calvin; Chhina, Jasdeep; Dar, Sajad A.; Morris, Robert T.; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R.; Rattan, Ramandeep

    2014-01-01

    A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer. PMID:25026276

  10. Unbalanced estrogen metabolism in ovarian cancer.

    PubMed

    Zahid, Muhammad; Beseler, Cheryl L; Hall, James B; LeVan, Tricia; Cavalieri, Ercole L; Rogan, Eleanor G

    2014-05-15

    Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer. PMID:24170413

  11. Homologous recombination deficiency and ovarian cancer.

    PubMed

    Ledermann, Jonathan A; Drew, Yvette; Kristeleit, Rebecca S

    2016-06-01

    The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation. PMID:27065456

  12. Diagnosis and Management of Ovarian Cancer.

    PubMed

    Doubeni, Chyke A; Doubeni, Anna R; Myers, Allison E

    2016-06-01

    Ovarian cancer is the most lethal gynecologic cancer. Less than one-half of patients survive for more than five years after diagnosis. Ovarian cancer affects women of all ages but is most commonly diagnosed after menopause. More than 75% of affected women are diagnosed at an advanced stage because early-stage disease is usually asymptomatic and symptoms of late-stage disease are nonspecific. The strongest risk factors are advancing age and family history of ovarian and breast cancer. Women who have symptoms concerning for ovarian cancer should undergo a physical examination, transvaginal ultrasonography, and measurement of biomarkers such as cancer antigen 125. If results are suspicious for ovarian cancer, the patient should be referred to a gynecologic oncologist. Despite the low rate of early diagnosis, guidelines recommend against routine screening for ovarian cancer in average-risk women because screening, including routine pelvic examinations, is ineffective and associated with harm. However, a recent trial found a potential benefit of annual screening using an algorithm based on serial cancer antigen 125 measurements followed by transvaginal ultrasonography for women at increased risk, as determined by the algorithm. Women with an increased-risk family history should be referred for genetic counseling and, if genetic mutations (e.g., BRCA mutations) are identified, bilateral salpingo-oophorectomy can be considered for risk reduction. In both average- and high-risk women, long-term hormonal contraceptive use reduces risk by about 50%. The treatment of ovarian cancer usually involves surgery, with or without intraperitoneal and intravenous chemotherapy. Primary care physicians have important roles in posttreatment surveillance and end-of-life care. PMID:27281838

  13. Features of ovarian cancer in Lynch syndrome (Review)

    PubMed Central

    NAKAMURA, KANAKO; BANNO, KOUJI; YANOKURA, MEGUMI; IIDA, MIHO; ADACHI, MASATAKA; MASUDA, KENTA; UEKI, ARISA; KOBAYASHI, YUSUKE; NOMURA, HIROYUKI; HIRASAWA, AKIRA; TOMINAGA, EIICHIRO; AOKI, DAISUKE

    2014-01-01

    Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9–2.7%. Lynch syndrome accounts for 10–15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65–75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome. PMID:25279173

  14. Short-Term PTEN Inhibition Improves In Vitro Activation of Primordial Follicles, Preserves Follicular Viability, and Restores AMH Levels in Cryopreserved Ovarian Tissue From Cancer Patients

    PubMed Central

    Novella-Maestre, Edurne; Herraiz, Sonia; Rodríguez-Iglesias, Beatriz; Díaz-García, César; Pellicer, Antonio

    2015-01-01

    Introduction In vitro activation and growth of primordial dormant follicles to produce fertilizable oocytes would provide a useful instrument for fertility preservation. The employment of Phosphatase and TENsin homolog (PTEN) inhibitors, in combination with Protein kinase B (Akt) stimulating molecules, has been previously employed to increase follicular activation through the stimulation of the PTEN-Akt pathway. Methods We aim to establish improved in vitro activation also for cancer patients whose ovarian tissue has already been cryopreserved. Fresh and previously cryopreserved human ovarian cortex were exposed to short-term, low-concentration and ovary-specific treatment with only a PTEN inhibitor. Results Our in vitro activation protocol enhances the activation mechanisms of primordial follicles in both fresh and cryopreserved samples, and enlarges growing populations without inducing apoptosis in either follicles or the surrounding stroma. Treatment augments estradiol secretion and restores the expression levels of the previously diminished Anti-Müllerian hormone by means of cryopreservation procedures. Genomic modulation of the relative expression of PTEN pathway genes was found in treated samples. Conclusion The in vitro activation protocol offers new alternatives for patients with cryopreserved tissue as it increases the pool of viable activated follicles available for in vitro growth procedures. The combination of ovarian tissue cryopreservation and in vitro activation of primordial follicles, the main ovarian reserve component, will be a major advancement in fertility preservation. PMID:26024525

  15. Three-dimensional modeling of ovarian cancer

    PubMed Central

    Erin, White; Hilary, Kenny; Ernst, Lengyel

    2015-01-01

    New models for epithelial ovarian cancer initiation and metastasis are required to obtain a mechanistic understanding of the disease and to develop new therapeutics. Modeling ovarian cancer however is challenging as a result of the genetic heterogeneity of the malignancy, the diverse pathology, the limited availability of human tissue for research, the atypical mechanisms of metastasis, and because the origin is unclear. Insights into the origin of high-grade serous ovarian carcinomas and mechanisms of metastasis have resulted in the generation of novel three-dimensional (3D) culture models that better approximate the behavior of the tumor cells in vivo than prior two-dimensional models. The 3D models aim to recapitulate the tumor microenvironment, which has a critical role in the pathogenesis of ovarian cancer. Ultimately, findings using models that accurately reflect human ovarian cancer biology are likely to translate into improved clinical outcomes. In this review we discuss the design of new 3D culture models of ovarian cancer primarily using human cells, key studies in which these models have been applied, current limitations, and future applications. PMID:25034878

  16. Cisplatin and Paclitaxel in Treating Patients With Stage IIB, Stage IIC, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cavity Cancer

    ClinicalTrials.gov

    2014-12-29

    Chemotherapeutic Agent Toxicity; Endometrial Adenocarcinoma; Fallopian Tube Carcinoma; Gastrointestinal Complication; Malignant Ovarian Mixed Epithelial Tumor; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage II Ovarian Cancer; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  17. Genetic heterogeneity of breast-ovarian cancer revisited

    SciTech Connect

    Narod, S.; Ford, D.; Easton, D.

    1995-10-01

    We have recently reported the results of a linkage analysis of 145 breast-ovarian cancer families. Each family has three or more cases of early-onset breast cancer (age {le}60) or of ovarian cancer, and all families have at least one case of ovarian cancer (there were nine site-specific ovarian cancer families). Overall, we estimated that 76% of the families were linked to the BRCA1 locus. 5 refs., 1 tab.

  18. Adoptive immunotherapy against ovarian cancer.

    PubMed

    Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

    2016-01-01

    The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting. PMID:27188274

  19. Ovarian stimulation in patients with breast cancer

    PubMed Central

    Muñoz, Elkin; González, Naira; Muñoz, Luis; Aguilar, Jesús; Velasco, Juan A García

    2015-01-01

    Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer

  20. Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in ovarian cancer

    PubMed Central

    Lin, Chi-Kang; Bai, Meng-Yi; Hu, Teh-Min; Wang, Yu-Chi; Chao, Tai-Kuang; Weng, Shao-Ju; Huang, Rui-Lan; Su, Po-Hsuan; Lai, Hung-Cheng

    2016-01-01

    Ovarian cancer treatment remains a challenge and targeting cancer stem cells presents a promising strategy. Niclosamide is an “old” antihelminthic drug that uncouples mitochondria of intestinal parasites. Although recent studies demonstrated that niclosamide could be a potential anticancer agent, its poor water solubility needs to be overcome before further preclinical and clinical investigations can be conducted. Therefore, we evaluated a novel nanosuspension of niclosamide (nano-NI) for its effect against ovarian cancer. Nano-NI effectively inhibited the growth of ovarian cancer cells in which it induced a metabolic shift to glycolysis at a concentration of less than 3 μM in vitro and suppressed tumor growth without obvious toxicity at an oral dose of 100 mg/kg in vivo. In a pharmacokinetic study after oral administration, nano-NI showed rapid absorption (reaching the maximum plasma concentration within 5 min) and improved the bioavailability (the estimated bioavailability for oral nano-NI was 25%). In conclusion, nano-NI has the potential to be a new treatment modality for ovarian cancer and, therefore, further clinical trials are warranted. PMID:26848771

  1. The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels.

    PubMed

    Alsina-Sanchis, Elisenda; Figueras, Agnès; Lahiguera, Álvaro; Vidal, August; Casanovas, Oriol; Graupera, Mariona; Villanueva, Alberto; Viñals, Francesc

    2016-10-15

    In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition. PMID:27299695

  2. Paclitaxel, Cisplatin, and Topotecan With or Without Filgrastim in Treating Patients With Newly Diagnosed Stage III or Stage IV Epithelial Ovarian Cancer

    ClinicalTrials.gov

    2013-01-23

    Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  3. Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells

    PubMed Central

    Choi, Jeong In; Park, Sang Hi; Lee, Hee-Jin; Lee, Dae Woo; Lee, Hae Nam

    2016-01-01

    Objective To identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells. Methods We used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures. Results Paclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells. Conclusion Addition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability. PMID:27148873

  4. Breast and Ovarian Cancer and Family History Risk Categories

    MedlinePlus

    ... Diseases Genomic Resources Breast and Ovarian Cancer and Family History Risk Categories Recommend on Facebook Tweet Share ... Screening. U.S. Preventive Services Task Force. February 2016. Family Health History, Breast and Ovarian Cancer Risk, and ...

  5. Does Breast or Ovarian Cancer Run in Your Family?

    MedlinePlus

    ... Does Breast or Ovarian Cancer Run in Your Family? Language: English Español (Spanish) Recommend on Facebook Tweet ... get ovarian cancer by age 70. Does Your Family Health History Put You At Risk? Tell your ...

  6. Two-Pronged Chemo Helps Some with Advanced Ovarian Cancer

    MedlinePlus

    ... html Two-Pronged Chemo Helps Some With Advanced Ovarian Cancer Study found using both abdomen drip and ... 4, 2016 (HealthDay News) -- Some women with advanced ovarian cancer may fare better if chemotherapy is dripped ...

  7. Effect of steroid hormones, estrogen and progesterone, on epithelial mesenchymal transition in ovarian cancer development.

    PubMed

    Jeon, So-Ye; Hwang, Kyung-A; Choi, Kyung-Chul

    2016-04-01

    As the primary female sex steroid hormones, estrogens and progesterone play important roles to regulate growth, differentiation, and function of a broad range of target tissues in the human body and maintain the function of female reproductive tissues. Ovarian cancer is the most cause of cancer death in gynecological malignancy. Despite enormous outcomes in the understanding of ovarian cancer pathology, this disease has resulted in poor survival rates since most patients are asymptomatic until the disease has been metastasized. The exact molecular events leading to metastasis of ovarian tumor cells have not yet been well elucidated, although it is recognized that the acquisition of capacity for migration and invasiveness would be a necessary prerequisite. During metastasis, epithelial-mesenchymal transition (EMT) is an important process, in which epithelial cells lose their intracellular adhesion and cell polarity and acquire increased motility and invasive properties to become mesenchymal like cells. The process of cancer cells to undergo EMT is regulated through the up- and down- regulation of a multiple cellular markers and signaling proteins. In this review, we focused the roles of women sex steroid hormones, estrogen and progesterone, in ovarian cancer, especially the ovarian cancer undergoing EMT and metastatic process. All things considered, we may suggest that progesterone is a potent hormone which inhibits the growth of human ovarian cancer cells and development to metastasis whereas estrogen may act as a risk factor of ovarian cancer progression and that progesterone therapy may be an alternative clinically effective tool for the treatment of human ovarian cancer. PMID:26873134

  8. Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling

    PubMed Central

    Lau, Wayne Bond; Lau, Bonnie; Luo, Zhongyue; Lin, Qiao; Yang, Huiliang; Xuan, Yu; Yi, Tao; Zhao, Xia; Wei, Yuquan

    2016-01-01

    Ovarian cancer constitutes one of the most lethal gynaecological malignancies worldwide and currently no satisfactory therapeutic approaches have been established. Therefore, elucidation of molecular mechanisms to develop targeted therapy of ovarian cancer is crucial. PDLIM2 is critical to promote ubiquitination of nuclear p65 and thus its role in inflammation has been highlighted recently. We demonstrate that PDLIM2 is decreased in both ovarian high-grade serous carcinoma and in various human ovarian cancer cell lines compared with normal ovary tissues and human ovarian surface epithelial cells (HOSE). Further functional analysis revealed that PDLIM2 is epigenetically repressed in ovarian cancer development and inhibition of PDLIM2 promoted ovarian cancer growth both in vivo and in vitro via NOS2-derived nitric oxide signaling, leading to recruitment of M2 type macrophages. These results suggest that PDLIM2 might be involved in ovarian cancer pathogenesis, which could serve as a promising therapeutic target for ovarian cancer patients. PMID:26593252

  9. Epidermal Growth Factor Receptor-Targeted Photosensitizer Selectively Inhibits EGFR Signaling and Induces Targeted Phototoxicity In Ovarian Cancer Cells

    PubMed Central

    Abu-Yousif, Adnan O.; Moor, Anne C. E.; Zheng, Xiang; Savellano, Mark D.; Yu, Weiping; Selbo, Pål K.; Hasan, Tayyaba

    2012-01-01

    Targeted photosensitizer delivery to EGFR expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyin monoacid ring A (BPD) was coupled to an EGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody. PMID:22266098

  10. Mucinous ovarian cancer: A therapeutic review.

    PubMed

    Xu, Wen; Rush, Jack; Rickett, Kirsty; Coward, Jermaine I G

    2016-06-01

    Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering 'GI style' chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations. PMID:27083591

  11. Olaparib in the management of ovarian cancer

    PubMed Central

    Bixel, Kristin; Hays, John L

    2015-01-01

    Alterations in the homologous repair pathway are thought to occur in 30%–50% of epithelial ovarian cancers. Cells deficient in homologous recombination rely on alternative pathways for DNA repair in order to survive, thereby providing a potential target for therapy. Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, capitalizes on this concept and is the first drug in its class approved for patients with ovarian cancer. This review article will provide an overview of the BRCA genes and homologous recombination, the role of PARP in DNA repair and the biological rationale for the use of PARP inhibitors as cancer therapy, and ultimately will focus on the use of olaparib in the management of ovarian cancer. PMID:26309417

  12. Sunitinib Malate in Treating Patients With Recurrent Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-01-15

    Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer

  13. CA125 in Ovarian Cancer

    PubMed Central

    Urban, Nicole

    2009-01-01

    Summary Twenty five years after its discovery, circulating CA125 antigen is recommended for clinical use in the US for ovarian cancer (OC) screening of high risk women with ovaries despite its limited sensitivity and specificity. Recent findings suggest that CA125 might also serve as a predictive marker for pre-invasive OC. Methods to quantify circulating CA125 evolved towards sensitive and reliable double determinant ELISA assays. The CA125 gene, MUC16, was cloned 20 years after the protein discovery and revealed a very complex and unusual glycoprotein structure suggesting an immunological role. Recent evidence points toward CA125 function in the induction of materno-fetal tolerance through the alteration of NK phenotype. Two receptors for CA125 have been described: mesothelin and galectin-1. The specific location and functional proprieties of CA125 make it a therapeutic target of choice; clinical trials have demonstrated that anti-CA125 injections are well tolerated and suggest a potential survival benefit. PMID:20477371

  14. KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine | Office of Cancer Genomics

    Cancer.gov

    Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells.

  15. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer.

    PubMed

    Zhang, Song-Fa; Wang, Xin-Yu; Fu, Zhi-Qin; Peng, Qiao-Hua; Zhang, Jian-Yang; Ye, Feng; Fu, Yun-Feng; Zhou, Cai-Yun; Lu, Wei-Guo; Cheng, Xiao-Dong; Xie, Xing

    2015-01-01

    Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(+)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics. PMID:25607466

  16. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

    PubMed Central

    Zhang, Song-Fa; Wang, Xin-Yu; Fu, Zhi-Qin; Peng, Qiao-Hua; Zhang, Jian-Yang; Ye, Feng; Fu, Yun-Feng; Zhou, Cai-Yun; Lu, Wei-Guo; Cheng, Xiao-Dong; Xie, Xing

    2015-01-01

    Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(+)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics. PMID:25607466

  17. Changes in Brain Function in Patients With Stage I, Stage II, Stage III, or Stage IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Who Are Receiving Chemotherapy

    ClinicalTrials.gov

    2016-02-09

    Cognitive Side Effects of Cancer Therapy; Malignant Ovarian Epithelial Tumor; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Choriocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Dysgerminoma; Ovarian Embryonal Carcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Germ Cell Tumor; Ovarian Mucinous Cystadenocarcinoma; Ovarian Polyembryoma; Ovarian Sarcoma; Ovarian Serous Cystadenocarcinoma; Ovarian Teratoma; Ovarian Yolk Sac Tumor; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IA Ovarian Germ Cell Tumor; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IB Ovarian Germ Cell Tumor; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IC Ovarian Germ Cell Tumor; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIC Ovarian Germ Cell Tumor; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  18. A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer

    PubMed Central

    Chen, Y. Ann; Coppola, Domenico; Reid, Brett M.; Lin, Hui-Yi; Teer, Jamie K.; Berchuck, Andrew; Birrer, Michael J.; Lawrenson, Kate; Monteiro, Alvaro N.A.; Schildkraut, Joellen M.; Goode, Ellen L.; Gayther, Simon A.; Sellers, Thomas A.; Cheng, Jin Q.

    2015-01-01

    The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants. PMID:26430965

  19. 3'-hydroxy-3,4,5,4'-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model.

    PubMed

    Piotrowska-Kempisty, Hanna; Ruciński, Marcin; Borys, Sylwia; Kucińska, Małgorzata; Kaczmarek, Mariusz; Zawierucha, Piotr; Wierzchowski, Marcin; Łażewski, Dawid; Murias, Marek; Jodynis-Liebert, Jadwiga

    2016-01-01

    In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4'-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment. PMID:27585955

  20. The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer

    PubMed Central

    Sheng, Xiugui; Han, Xiaoyun; Schointuch, Monica N.; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae-Jump, Victoria L.

    2016-01-01

    Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials. PMID:26503475

  1. Ovarian cancer treatment: The end of empiricism?

    PubMed

    Lheureux, Stephanie; Karakasis, Katherine; Kohn, Elise C; Oza, Amit M

    2015-09-15

    The diagnosis, investigation, and management of ovarian cancer are in a state of flux-balancing ever rapid advances in our understanding of its biology with 3 decades of clinical trials. Clinical trials that started with empirically driven selections have evolved in an evidence-informed manner to gradually improve outcome. Has this improved understanding of the biology and associated calls to action led to appropriate changes in therapy? In this review, the authors discuss incorporating emerging data on biology, combinations, dose, and scheduling of new and existing agents with patient preferences in the management of women with ovarian cancer. PMID:26096019

  2. Estrogen inhibits cell cycle progression and retinoblastoma phosphorylation in rhesus ovarian surface epithelial cell culture

    SciTech Connect

    Wright, Jay W.; Stouffer, Richard L.; Rodland, Karin D.

    2003-10-31

    Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1μg/ml). OSE cells express the estrogen receptor (ER)-α, and are the source of 90% of various cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentration of estradiol and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.

  3. Paclitaxel and Carboplatin With or Without Bevacizumab in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-12-21

    Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinofibroma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  4. Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens

    PubMed Central

    Cramer, Daniel W.; Bast, Robert C.; Berg, Christine D.; Diamandis, Eleftherios P.; Godwin, Andrew K.; Hartge, Patricia; Lokshin, Anna E.; Lu, Karen H.; McIntosh, Martin W.; Mor, Gil; Patriotis, Christos; Pinsky, Paul F.; Thornquist, Mark D.; Scholler, Nathalie; Skates, Steven J.; Sluss, Patrick M.; Srivastava, Sudhir; Ward, David C.; Zhang, Zhen; Zhu, Claire S.; Urban, Nicole

    2011-01-01

    Establishing a cancer screening biomarker’s intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network (EDRN) or Ovarian Cancer Specialized Program of Research Excellence (SPORE) sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within six months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. PMID:21372036

  5. Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling.

    PubMed

    Xia, Rong; Chen, Sun-Xiao; Qin, Qin; Chen, Yan; Zhang, Wei-Wei; Zhu, Rong-Rong; Deng, An-Mei

    2016-01-01

    Oridonin, an ent-kaurane diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, has shown various pharmacological and physiological effects such as anti-tumor, anti-bacterial, and anti-inflammatory properties. However, the effect of oridonin on human ovarian cancer cell lines has not been determined. In this study, we demonstrated that oridonin inhibited ovarian cancer cell proliferation, migration and invasion in a dose-dependent manner. Furthermore, we showed oridonin inhibited tumor growth of ovarian cancer cells (SKOV3) in vivo. We then assessed mechanisms and found that oridonin specifically abrogated the phosphorylation/activation of mTOR signaling. In summary, our results indicate that oridonin is a potential inhibitor of ovarian cancer by blocking the mTOR signaling pathway. PMID:26925661

  6. Hypodontia and ovarian cancer: A systematic review

    PubMed Central

    Iavazzo, Christos; Papakiritsis, Matthaios; Gkegkes, Ioannis D.

    2016-01-01

    Hypodontia can be defined as the non-formation of one or more teeth during the developmental period. Mutation in several genes related to tooth formation has previously been correlated with cancer. Regarding the ovarian cancer, there are few studies that associate the presence of hypodontia with ovarian cancer. A systematic literature search was performed in PubMed and Scopus. In total, 385 patients were included in this study. Control group was present in 3 out of 4 studies (340 patients). Hypodontia was present in 56 out of 290 patients (incidence of 19.3%). Only in 2 out of 4 studies, the number of missing teeth was mentioned (47 teeth), while the majority of them were either maxillary second premolars or maxillary lateral incisors. Unilateral distribution of the missing teeth was present in 28 out of 46 patients, while bilateral distribution of the missing teeth was present in 18 out of 46 patients. The presence of ovarian cancer in the family medical history occurred in 12 out of 33 patients. Only 1 out of 4 studies examined the presence of genes with mutations in the included patients. Based on our findings, the lack of clinical studies was the principal obstacle to clarify the possible predictive value of hypodontia in the early prediction of patients with higher risk of ovarian cancer. PMID:27026778

  7. BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9

    PubMed Central

    Qin, Yunlong; Xu, Jingyao; Aysola, Kartik; Oprea, Gabriela; Reddy, Avinash; Matthews, Roland; Okoli, Joel; Cantor, Alan; Grizzle, William E; Partridge, Edward E; Reddy, E Shyam P; Landen, Charles; Rao, Veena N

    2012-01-01

    Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers. PMID:22957306

  8. [Immunological analogies between ovarian cancer and pregnancy].

    PubMed

    Hanssen, S; Collinet, P; Leblanc, E; Salzet, M; Vinatier, D

    2013-05-01

    During pregnancy an environment allowing installation of tolerance toward the fetus is set up locally at the materno-fetal interface. Numerous effectors of immunity are involved in this tolerance (NK cell, T cell, Macrophages, dendritic cell). Specific mechanisms during pregnancy attract locally these immunological cells. In the decidua, they are educated toward tolerance. These mechanisms evolve during the pregnancy because at the end of the pregnancy, tolerance is broken to prepare and activate the labor. Ovarian tumors, after having surmounted the immunosurveillance, like trophoblast, chair the installation of a tolerance of their host facilitating the development of the disease. The blocking of these mechanisms of tolerance coupled with activation of mechanisms of defenses offer new perspectives in the treatment of the ovarian cancer. The authors suggest showing the analogies of the tolerance observed during ovarian cancer and pregnancy. The knowledge of the orchestration of the physiological mechanisms observed during pregnancy will offer new therapeutic targets. PMID:23182791

  9. NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms

    PubMed Central

    Yu, Yinhua; Mao, Weiqun; Wang, Yan; Baggerly, Keith; Wang, Ying; Marquez, Rebecca T.; Bedi, Anuja; Liu, Jinsong; Fishman, David; Lu, Zhen; Bast, Robert C.

    2016-01-01

    NDN is a maternally imprinted gene consistently expressed in normal ovarian epithelium, is dramatically downregulated in the majority of ovarian cancers. Little or no NDN expression could be detected in 73% of 351 epithelial ovarian cancers. NDN was also downregulated in 10 ovarian cancer cell lines with total loss in 6 of 10. Re-expression of NDN decreased Bcl-2 levels and induced apoptosis, which significantly inhibited ovarian cancer cell growth in cell culture and in xenografts. In addition, re-expression of NDN inhibited cell migration by decreasing actin stress fiber and focal adhesion complex formation through deactivation of Src, FAK and RhoA. Loss of NDN expression in ovarian cancers could be attributed to LOH in 28% of 18 informative cases and to hypermethylation of CpG sites 1 and 2 of NDN promoter in 23% and 30% of 43 ovarian cancers, respectively. Promoter hypermethylation was also found in 5 of 10 ovarian cancer cell lines. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored NDN expression in 4 of 7 cell lines with enhanced promoter methylation levels. These observations support the conclusion that NDN is an imprinted tumor suppressor gene which affects cancer cell motility, invasion and growth and that its loss of function in ovarian cancer can be caused by both genetic and epigenetic mechanisms. PMID:26689988

  10. Dasatinib Induces Autophagic Cell Death in Human Ovarian Cancer*

    PubMed Central

    Le, Xiao-Feng; Mao, Weiqun; Lu, Zhen; Carter, Bing Z.; Bast, Robert C.

    2010-01-01

    BACKGROUND Dasatinib, an inhibitor of Src/Abl family kinases, can inhibit tumor growth of a number of solid tumors. However, the effect and mechanism of action of dasatinib in human ovarian cancer cells remains unknown. METHODS Dasatinib-induced autophagy was determined by acridine orange staining, punctate localization of GFP-LC3, LC3 protein blotting and electron microscopy. Significance of Beclin-1, AKT and Bcl-2 in dasatinib-induced autophagy and growth inhibition was assayed by small interfering RNA silencing and/or overexpression of gene of interest. RESULTS Dasatinib inhibited cell growth by inducing little apoptosis, but substantial autophagy in SKOv3 and HEY ovarian cancer cells. In vivo studies showed dasatinib inhibited tumor growth and induced both autophagy and apoptosis in a HEY xenograft model. Knockdown of Beclin 1 and Atg12 expression with their respective siRNAs diminished dasatinib-induced autophagy, whereas knockdown of p27Kip1 with specific siRNAs did not. shRNA knockdown of Beclin-1 expression reduced dasatinib-induced autophagy and growth inhibition. Dasatinib reduced the phosphorylation of AKT, mTOR, p70S6K and S6 kinase expression. Constitutive expression of AKT1 and AKT2 inhibited dasatinib-induced autophagy in both HEY and SKOv3 cells. Dasatinib also reduced Bcl-2 expression and activity. Overexpression of Bcl-2 partially prevented dasatinib-induced autophagy. CONCLUSIONS We conclude that dasatinib induces autophagic cell death in ovarian cancer that partially depends on Beclin-1, AKT and Bcl-2. These results may have implications for clinical use of dasatinib. PMID:20629079

  11. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion.

    PubMed

    Griner, Samantha E; Joshi, Jayashree P; Nahta, Rita

    2013-01-01

    Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. PMID:23085437

  12. Quality of Life and Care Needs of Patients With Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Peritoneal Cancer

    ClinicalTrials.gov

    2016-03-17

    Anxiety; Fatigue; Nausea and Vomiting; Neurotoxicity Syndrome; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IB Fallopian Tube Cancer; Stage IC Fallopian Tube Cancer; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIB Fallopian Tube Cancer; Stage IIC Fallopian Tube Cancer; Stage III Ovarian Cancer; Stage III Primary Peritoneal Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIC Fallopian Tube Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  13. Targeting the EGF Receptor for Ovarian Cancer Therapy

    PubMed Central

    Zeineldin, Reema; Muller, Carolyn Y.; Stack, M. Sharon; Hudson, Laurie G.

    2010-01-01

    Ovarian carcinoma is the leading cause of death from gynecologic malignancy in the US. Factors such as the molecular heterogeneity of ovarian tumors and frequent diagnosis at advanced stages hamper effective disease treatment. There is growing emphasis on the identification and development of targeted therapies to disrupt molecular pathways in cancer. The epidermal growth factor (EGF) receptor is one such protein target with potential utility in the management of ovarian cancer. This paper will discuss contributions of EGF receptor activation to ovarian cancer pathogenesis and the status of EGF receptor inhibitors and EGF receptor targeted therapies in ovarian cancer treatment. PMID:20066160

  14. Microvesicles as Potential Ovarian Cancer Biomarkers

    PubMed Central

    Giusti, Ilaria; D'Ascenzo, Sandra; Dolo, Vincenza

    2013-01-01

    Although the incidence of ovarian cancer is low (i.e., less than 5% in European countries), it is the most lethal gynecologic malignancy and typically has a poor prognosis. To ensure optimal survival, it is important to diagnose this condition when the pathology is confined to the ovary. However, this is difficult to achieve because the first specific symptoms appear only during advanced disease stages. To date, the biomarker mainly used for the diagnosis and prognosis of ovarian cancer is CA125; however, this marker has a low sensitivity and specificity and is associated with several other physiological and pathological conditions. No other serum ovarian cancer markers appear to be able to replace or complement CA125, and the current challenge is therefore to identify novel markers for the early diagnosis of this disease. For this purpose, studies have focused on the microvesicles (MVs) released from tumor cells. MVs may represent an ideal biomarker because they can be easily isolated from blood, and they have particular features (mainly regarding microRNA profiles) that strongly correlate with ovarian cancer stage and may be effective for early diagnosis. PMID:23484144

  15. Surgical management of recurrent ovarian cancer.

    PubMed

    Suh, Dong Hoon; Kim, Hee Seung; Chang, Suk-Joon; Bristow, Robert E

    2016-08-01

    Most patients with advanced-stage epithelial ovarian cancer will experience a relapse of disease despite a complete response after surgical cytoreduction and platinum-based chemotherapy. Treatment of recurrent ovarian cancer mainly comprises various combinations of systemic chemotherapy with or without targeted agents. The role of cytoreductive surgery for recurrent ovarian cancer is not well established. Although the literature on survival benefit of cytoreductive surgery for recurrent disease has expanded steadily over the past decade, most studies were retrospective, single-institution series with small numbers of patients. Given the balance between survival benefit and surgery-related morbidity during maximum cytoreductive surgical effort, it is essential to establish the optimal selection criteria for identifying appropriate candidates who will benefit from surgery without worsening quality of life. Three phase III randomized trials for this issue are currently underway. Herein, we present contemporary evidence supporting the positive role of cytoreductive surgery and offer selection criteria for optimal candidates for surgery in the treatment of recurrent ovarian cancer. PMID:27130407

  16. Targeted Immune Therapy of Ovarian Cancer

    PubMed Central

    Knutson, Keith L.; Karyampudi, Lavakumar; Lamichhane, Purushottam; Preston, Claudia

    2014-01-01

    Clinical outcomes, such as recurrence free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathologic network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies. PMID:25544369

  17. Ovarian Cancer Rates by Race and Ethnicity

    MedlinePlus

    ... any other group, followed by black, Hispanic, American Indian/Alaska Native, and Asian/Pacific Islander women. Ovarian Cancer Death Rates* by Race and Ethnicity, U.S., 1999–2012 Mortality source: U.S. Mortality Files, National Center for Health ...

  18. Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal ... primary peritoneal cancer that are not listed here. Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal ...

  19. MiR-34a suppresses ovarian cancer proliferation and motility by targeting AXL.

    PubMed

    Li, Rui; Shi, Xuejun; Ling, Fengyu; Wang, Chunguang; Liu, Junxia; Wang, Wei; Li, Ming

    2015-09-01

    Increasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to tumor progression. The miR-34 family is directly transactivated by tumor suppressor p53 which is frequently mutated in various cancers; however, the effect of miR-34a on the ovarian cancer cells remains unclear. The aim of the paper was to study the expression of miR-34a in ovarian cancer and miR-34a's relation to the cell proliferation and metastasis in ovarian cancer in vitro. miR-34a expression was determined by quantitative RT-PCR in a panel of 60 human ovarian cancer samples. Functional characterization of miR-34a was accomplished by reconstitution of miR-34a expression in ovarian cancer cells by determining changes in proliferation, migration, and invasion. Our results showed that miR-34a is downregulated in ovarian cancer tissues compared with the corresponding adjacent non-neoplastic tissues, and the expression level of miR-34a was significantly lower in ovarian cancer cell lines in comparison with normal human fallopian tube epithelial cell line. The 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay revealed significant cell proliferation inhibition in miR-34a transfectant compared with the control from HO8910 and SKOV3 cells, which displayed lowest expressions of miR-34a. Furthermore, the transwell assay also showed significant cell migration inhibition in miR-34a transfectant, compared with cell lines transfected with NC. Overexpression of miR-34a led to the inhibition of AXL expression, indicating that AXL is a target gene for miR-34a. Our data suggest that miR-34a may function as a tumor suppressor through repression of oncogenic AXL in ovarian cancer. PMID:25895459

  20. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility and proliferation, but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.

  1. Ovarian cancer treatment: The end of empiricism?

    PubMed Central

    Lheureux, Stephanie; Karakasis, Katherine; Kohn, Elise C.

    2015-01-01

    The diagnosis, investigation, and management of ovarian cancer are in a state of flux—balancing ever rapid advances in our understanding of its biology with 3 decades of clinical trials. Clinical trials that started with empirically driven selections have evolved in an evidence‐informed manner to gradually improve outcome. Has this improved understanding of the biology and associated calls to action led to appropriate changes in therapy? In this review, the authors discuss incorporating emerging data on biology, combinations, dose, and scheduling of new and existing agents with patient preferences in the management of women with ovarian cancer. Cancer 2015;121:3203–3211. © 2015 American Cancer Society. PMID:26096019

  2. Interleukin 6 Receptor Is an Independent Prognostic Factor and a Potential Therapeutic Target of Ovarian Cancer

    PubMed Central

    Isobe, Aki; Sawada, Kenjiro; Kinose, Yasuto; Ohyagi-Hara, Chifumi; Nakatsuka, Erika; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Mabuchi, Seiji; Ohta, Tsuyoshi; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

    2015-01-01

    Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment. PMID:25658637

  3. Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-05-22

    Chemotherapeutic Agent Toxicity; Neuropathy; Neurotoxicity Syndrome; Pain; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  4. The immunomodulating roles of glycoproteins in epithelial ovarian cancer

    PubMed Central

    Patankar, Manish S.; Gubbels, Jennifer A.A.; Felder, Mildred; Connor, Joseph P.

    2015-01-01

    The complexity of the immune system demands an intricate defense mechanism by tumors. Ovarian and other tumors employ specific glycoproteins and the associated glycan sequences to modulate immune responses. Glycoproteins enable tumor cells that express or secrete these molecules to evade immune cell attack and induce the immune system to promote tumor growth. This review focuses first on the immune environment in ovarian cancer, and the mechanisms of activation and inhibition that immune cells undergo in order to either attack or ignore a target cell. Next we illustrate the immunomodulatory roles of ovarian cancer-associated glycans and glycoproteins in 1. preventing immune synapse formation, 2. serving as ligands of immune cell receptors, 3. scavenging cytokines and chemokines, and 4. participating in the formation of autoantibodies against the tumor. The importance of these immunomodulating strategies from the view points of understanding the tumor immunology of ovarian tumors, potential origin of such mechanisms, and specific strategies to circumvent the glycoconjugate-mediated suppression of immune responses is discussed in this review. PMID:22201900

  5. YY1 modulates taxane response in epithelial ovarian cancer

    PubMed Central

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, Joe W.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2009-01-01

    Purpose Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Experimental design Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Results Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility and proliferation, but also increases resistance to taxanes, with no effect on cisplatin sensitivity. Conclusions These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function. PMID:19208743

  6. Gene expression profiling analysis of ovarian cancer

    PubMed Central

    YIN, JI-GANG; LIU, XIAN-YING; WANG, BIN; WANG, DAN-YANG; WEI, MAN; FANG, HUA; XIANG, MEI

    2016-01-01

    As a gynecological oncology, ovarian cancer has high incidence and mortality. To study the mechanisms of ovarian cancer, the present study analyzed the GSE37582 microarray. GSE37582 was downloaded from Gene Expression Omnibus and included data from 74 ovarian cancer cases and 47 healthy controls. The differentially-expressed genes (DEGs) were screened using linear models for microarray data package in R and were further screened for functional annotation. Next, Gene Ontology and pathway enrichment analysis of the DEGs was conducted. The interaction associations of the proteins encoded by the DEGs were searched using the Search Tool for the Retrieval of Interacting Genes, and the protein-protein interaction (PPI) network was visualized by Cytoscape. Moreover, module analysis of the PPI network was performed using the BioNet analysis tool in R. A total of 284 DEGs were screened, consisting of 145 upregulated genes and 139 downregulated genes. In particular, downregulated FBJ murine osteosarcoma viral oncogene homolog (FOS) was an oncogene, while downregulated cyclin-dependent kinase inhibitor 1A (CDKN1A) was a tumor suppressor gene and upregulated cluster of differentiation 44 (CD44) was classed as an ‘other’ gene. The enriched functions included collagen catabolic process, stress-activated mitogen-activated protein kinases cascade and insulin receptor signaling pathway. Meanwhile, FOS (degree, 15), CD44 (degree, 9), B-cell CLL/lymphoma 2 (BCL2; degree, 7), CDKN1A (degree, 7) and matrix metallopeptidase 3 (MMP3; degree, 6) had higher connectivity degrees in the PPI network for the DEGs. These genes may be involved in ovarian cancer by interacting with other genes in the module of the PPI network (e.g., BCL2-FOS, BCL2-CDKN1A, FOS-CDKN1A, FOS-CD44, MMP3-MMP7 and MMP7-CD44). Overall, BCL2, FOS, CDKN1A, CD44, MMP3 and MMP7 may be correlated with ovarian cancer. PMID:27347159

  7. Cisplatin induces stemness in ovarian cancer.

    PubMed

    Wiechert, Andrew; Saygin, Caner; Thiagarajan, Praveena S; Rao, Vinay S; Hale, James S; Gupta, Nikhil; Hitomi, Masahiro; Nagaraj, Anil Belur; DiFeo, Analisa; Lathia, Justin D; Reizes, Ofer

    2016-05-24

    The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility. PMID:27105520

  8. Pentamethylpyrromethene boron difluoride complexes in human ovarian cancer photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Morgan, Lee R.; Chaudhuri, Aulena; Gillen, Laura E.; Boyer, Joseph H.; Wolford, Lionel T.

    1990-07-01

    Quasiaromatic heterocycles (QAM) such as substituted 1 , 3 , 5 , 7 , 8-pentamethylpyrromethene boron difluorides (PMP-BF2) and - (dimethoxyphosphinylmethyl, methyl) bimane have been evaluated for their abilities to produce cellular toxicities when used in photodynamic therapy (PDT) for ovarian cancer. The most active QAH tested to date has been the disodiuxn salt of PMP-2,6-disulfonate--BF2 (PMPDS-BF2). Human ovarian cancer cells from fifteen different patients have been grown in culture. Cells were obtained from biopsy material and grown in RPMI medium with 10% FBA plus penicillin and streptomycin. Cells were harvested and as single cell suspensions exposed to PMP-BF2 complexes or bimanes in concentrations of 0.004-0.4 ug/106 cells/ml of medium. Initially the cells were exposed to the chemicals for 30 minutes in a 5% CO2 incubator (37°C) with gentle shaking. The cells were washed with plain RPMI medium, then resuspended in the enriched RPMI medium and exposed to a sunlamp for 10-20 minutes. Cells were then allowed to grow in an soft agar culture media at 37°C (5% C02) for 14 days. When compared to controls (only light or only chemicals) there was 100% inhibition of all cellular growth for PMPDSBF2 at the 0.4 ug/mi concentrations. There was variations in concentrations of the chemical needed to produce 100% inhibition when the 15 different ovarian cancer cell specimens were compared at all concentrations. PMP-BF2 complexes are characterized by extremely high extinction coefficients, superior laser activity and little if any triplet-triplet absorption. The biamanes share these properties however are less active in ovarian cancer cell The lasing properties of PMP-BF2, and bimanes will be compared to their PDT effectiveness.

  9. Familial ovarian cancer: a study of 11 families.

    PubMed

    Villani, C; Ficorella, C; Tomao, S

    1989-01-01

    In a group of 152 ovarian cancer patients, 11 cases with familial recurrence were investigated (7.23%). Of the families evaluated we found 26 patients with ovarian cancer and twenty two with different cancers in other sites. In ovarian cancer the familial aspect, despite its relatively low frequency, is one of the few factors for identifying "high risk" patients, thus allowing effective secondary prevention. PMID:2776785

  10. [Treatment of brain metastasis from ovarian cancer].

    PubMed

    Bondiau, P-Y; Largillier, R; Foa, C; Rasendrarijao, D; Frenay, M; Gérard, J-P

    2003-06-01

    Systemic metastases from ovarian carcinoma are frequent, but they seldom affect the central nervous system. We present here the case of a patient treated for an ovarian cancer by surgery and chemotherapy. Three months after the end of chemotherapy, the patient developed cerebral metastases from ovarian carcinoma (CMOC) treated by iterative surgery and and whole brain irradiation. As the frequency of solitary cerebral metastasis of ovarian cancer is higher than with other cancers, it is likely that they behave slightly differently. Literature analysis reveals an increase in the incidence of CMOC since the middle of the nineties. CMOC can occur during or after adjuvant chemotherapy and the best management strategies to better define determinants of survival for patients are not well known. It appears that a better outcome of CMOC may be obtained by an aggressive treatment, if possible, including surgery, radiotherapy, and chemotherapy. Taking into account the increase in the incidence of the CMOC and their early occurrence, some authors have proposed a prophylactic brain radiotherapy in patients who receive adjuvant chemotherapy. PMID:12834774

  11. Sargramostim and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Advanced Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer That Did Not Respond to Previous Chemotherapy

    ClinicalTrials.gov

    2014-01-15

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  12. Second-look laparoscopy in ovarian cancer.

    PubMed

    Xygakis, A M; Politis, G S; Michalas, S P; Kaskarelis, D B

    1984-08-01

    Forty-six patients with epithelial ovarian cancer previously treated with surgery, chemotherapy or external radiation underwent second-look laparoscopy to evaluate management. Twenty of the patients had positive laparoscopic findings and were not subjected to further laparotomy. The frequency of positive findings was related to the stage of the disease. Laparoscopic examination revealed no evidence of cancer in the remaining 26 patients. Three of the patients in this group were found to have additional disease at subsequent laparotomy. The laparoscopic procedures were not associated with major complications. Although second-look laparoscopy cannot replace repeat laparotomy, it does have a role in the follow-up of patients with ovarian cancer. PMID:6237197

  13. Clinical Efficacy of Ovarian Cancer Screening

    PubMed Central

    Koshiyama, Masafumi; Matsumura, Noriomi; Konishi, Ikuo

    2016-01-01

    Various trials of ovarian cancer screening programs have been reported worldwide. In 2011, one of the most famous papers indicated that annual screening using CA125/transvaginal sonography (TVS) did not reduce ovarian cancer mortality in the United States of America (USA). To investigate the validity of ovarian cancer screening, we verified the analyses of previous reports. At first, we obtained the USA datasets that were used for the analyses and identified many patients in whom cancers were accidentally detected several years after the screening period. We thus performed a new prognostic comparison between the screening group (cancers that were detected through screening or within one year after screening) and the control group (cancers that were found more than one year after screening, without screening, or in the original control group). The results showed that the prognoses of the screening group were significantly better than those of the control group (p=0.0017). In addition, the screening group contained significantly fewer stage IV cases than the control group (p=0.005). In another screening in the United Kingdom, ovarian cancer was detected at a relatively earlier stage (stage I/II: 44%), while the rate of stage IV detection was low (4%). Very recently, this team showed significant difference in the rates with and without screening (p=0.021) when prevalent cases were excluded and indicated the delayed effect of screening. These results contrasted with the USA data. In other studies in the USA and Japan, annual screening was also associated with a decreased stage at detection. New histopathological, molecular and genetic studies have recently provided two categories of ovarian carcinogenesis. Type I carcinomas are slow-growing neoplasms that often develop from benign ovarian cysts. Type II carcinomas are high-grade clinically aggressive neoplasms. The rate of type II carcinomas is significantly higher in Europe and the USA than in Asia (p<0

  14. Ovarian cancer proteomics: Many technologies one goal.

    PubMed

    Narasimhan, Kothandaraman; Changqing, Zhao; Choolani, Mahesh

    2008-02-01

    The last decade has seen major changes in the technologies used to identify markers for diagnosing cancer. This review focuses on recent developments on the evolving field of biomarker discovery, and validation techniques using proteomics platforms for ovarian cancer. It is possible now to diagnose various disease conditions using microliter quantities of body fluids. Currently the major developments were made in three distinct areas: (i) protein profiling, (ii) high-throughput validation techniques, and (iii) solid and liquid phase protein microarray platforms for analyzing candidate markers across subclasses and stages of cancers. The recent addition to the long list of technologies is metabolomics using metabolite profiling and informatics-based filtering of information for biomarker discovery of ovarian cancer. Emerging technologies need to address ways to eliminate the limitations posed by the complex dynamic nature of body fluids as well as ways to enrich low-abundance tumor markers if they were to become a successful biomarker discovery tool. These new technologies hold significant promise in identifying more robust markers for ovarian cancer. Since the prevalence of this disease in the population is low, the test must have a high specificity. PMID:21136825

  15. Ovarian Cancer Rates by State

    MedlinePlus

    ... Controls Search The CDC Cancel Submit Search The CDC Gynecologic Cancers Note: Javascript is disabled or is not supported ... about this message, please visit this page: About CDC.gov . Gynecologic Cancers Basic Information What Is Gynecologic Cancer? What Are ...

  16. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    SciTech Connect

    Choi, Yoon Pyo; Kim, Baek Gil; Gao, Ming-Qing; Kang, Suki; Cho, Nam Hoon

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  17. Resveratrol attenuates norepinephrine-induced ovarian cancer invasiveness through downregulating hTERT expression.

    PubMed

    Kim, Seung Hwa; Cho, Kyung Hwa; Kim, Yu Na; Jeong, Bo Young; Park, Chang Gyo; Hur, Gang Min; Lee, Hoi Young

    2016-02-01

    Stress hormone norepinephrine (NE) has been associated with acquisition of cancer progression, and naturally occurring phytoalexin resveratrol (REV) has been known to suppress cancer growth and progression. In the present study, we determine the effect of REV on NE-induced ovarian cancer invasiveness. Pretreatment of REV significantly inhibited NE-induced ovarian cancer cell epithelial-to-mesenchymal transition with concomitant recovery of E-cadherin expression. In addition, our data showed that REV downregulates NE-induced human telomerase reverse transcriptase (hTERT) expression through inhibiting Src phosphorylation and HIF-1α expression. Further, REV reduced NE-induced Slug expression and subsequent ovarian cancer invasion. More importantly, combined treatment of REV with a pharmacological inhibitor of beta adrenergic receptor significantly attenuated NE-induced ovarian cancer invasion compared to single treatment. Therefore, we demonstrate interference of a Src and HIF-1α/hTERT/Slug signaling cascade by REV, providing potential therapeutic targets and inhibition of ovarian cancer. PMID:26428673

  18. Piperlongumine induces apoptosis and synergizes with cisplatin or paclitaxel in human ovarian cancer cells.

    PubMed

    Gong, Li-Hua; Chen, Xiu-Xiu; Wang, Huan; Jiang, Qi-Wei; Pan, Shi-Shi; Qiu, Jian-Ge; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Zheng, Fei-Yun; Shi, Zhi; Yan, Xiao-Jian

    2014-01-01

    Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer. PMID:24895529

  19. Piperlongumine Induces Apoptosis and Synergizes with Cisplatin or Paclitaxel in Human Ovarian Cancer Cells

    PubMed Central

    Chen, Xiu-Xiu; Wang, Huan; Jiang, Qi-Wei; Pan, Shi-Shi; Qiu, Jian-Ge; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Zheng, Fei-Yun; Yan, Xiao-Jian

    2014-01-01

    Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer. PMID:24895529

  20. The Therapeutic Potential of Class I Selective Histone Deacetylase Inhibitors in Ovarian Cancer

    PubMed Central

    Khabele, Dineo

    2014-01-01

    Epithelial ovarian cancer remains the deadliest gynecologic malignancy. Despite advances in treatment, new approaches are needed. Histone deacetylases (HDACs) are a family of enzymes that regulate gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Inhibition of HDACs with small molecules has led to the development of histone deacetylase inhibitors (HDACi) that are in clinical use, primarily for hematologic malignancies. Although clinical trials with HDACi as single agents in solid tumors have been disappointing, data from independent labs and recent work by our group show that class I selective HDACi have potent anti-tumor effects in pre-clinical models of ovarian cancer. This review summarizes the role of HDACs in ovarian cancer and the potential niche for selective class I HDACi, particularly HDAC3 in ovarian cancer therapy. PMID:24904826

  1. MicroRNAs in Ovarian Cancer.

    PubMed

    Katz, Betina; Tropé, Claes G; Reich, Reuven; Davidson, Ben

    2015-09-01

    Ovarian cancer, consisting predominantly of ovarian carcinoma, is the eighth most common cancer in women and the most lethal gynecologic malignancy. Efforts focus on identifying biomarkers which may aid in early diagnosis and reduce mortality, as well as on characterizing therapeutic targets with the aim of circumventing chemoresistance and prolonging survival at advanced-stage disease. MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression, and have been found to play an important role in ovarian carcinoma. Recent research has identified multiple miRNAs involved in the biology and progression of the disease, and supports a role for miRNAs as potential biomarkers, predictive markers and prognostic factors. Many of the studies published to date nevertheless suffer from critical weaknesses which affect data quality and reproducibility, including the comparison of normal ovaries to tumor tissue without compensation for the highly discrepant target cell fraction in these two specimen types and the inclusion of carcinomas of different histotypes, non-epithelial tumors or tumors of non-specified histology. These shortcomings highlight the critical role of pathologists as part of the team in the setting of such research. This review summarizes current knowledge in this area and discusses the potential clinical relevance of miRNAs in ovarian carcinoma, with focus on studies of clinical specimens in which tissue selection has been deemed adequate. PMID:26216350

  2. Hormone Therapy and Ovarian Cancer: Incidence and Survival

    PubMed Central

    Wernli, Karen J.; Newcomb, Polly A.; Hampton, John; Trentham-Dietz, Amy; Egan, Kathleen M.

    2009-01-01

    Objective We conducted a population-based case-control study to investigate the association between hormone therapy (HT) and ovarian cancer incidence, and followed all these cancer cases to determine the association of HT use with ovarian cancer mortality. Methods Seven hundred fifty-one incident cases of invasive epithelial ovarian cancer aged 40–79 years were diagnosed in Wisconsin and Massachusetts between 1993–1995 and 1998–2001 and matched to similarly-aged controls (n=5808). Study subjects were interviewed by telephone, which ascertained information on HT use and specific preparation, estrogen alone (E-alone) or estrogen plus progestin (EP). Ovarian cancer cases were followed-up for mortality through December 2005. Multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals (CI) for ovarian cancer incidence, and Cox proportional hazards modeling was used to estimate hazard ratios and corresponding confidence intervals for ovarian cancer mortality. Results Ever use of HT was significantly associated with an increased risk of ovarian cancer (odds ratio 1.57, 95% CI 1.31–1.87). The excess risk was confined to women who used E-alone preparations (OR 2.33, 95% CI 1.85–2.95). No significant associations were detected between pre-diagnosis HT use and ovarian cancer survival. Conclusions Hormone therapy increases risk of ovarian cancer among E-alone users, but there is no substantial impact on survival after diagnosis. PMID:18264784

  3. miR-132 targeting E2F5 suppresses cell proliferation, invasion, migration in ovarian cancer cells

    PubMed Central

    Tian, Hang; Hou, Lei; Xiong, Yu-Mei; Huang, Jun-Xiang; Zhang, Wen-Hua; Pan, Yong-Ying; Song, Xing-Rong

    2016-01-01

    Accumulating evidence showed that microRNA-132 (miR-132) are involved in development and progression of several types of cancers, however, the function and underlying molecular mechanism of miR-132 in ovarian cancer remains unclear. In this study we investigated the biological roles and molecular mechanism of miR-132 in ovarian cancer. Here, we found that that the expression levels of miR-132 were dramatically decreased in ovarian cancer cell lines and clinical ovarian cancer tissue samples. Then, we found that introduction of miR-132 significantly suppressed the proliferation, colony formation, migration and invasion of ovarian cancer cells. Mechanism investigation revealed that miR-132 inhibited the expression of transcription factor E2F5 by specifically targeting its mRNA 3’UTR. Moreover, the expression level of E2F5 was significantly increased in ovarian cancer tissues than in the adjacent normal tissues, and its expression was inversely correlated with miR-132 expression in clinical ovarian cancer tissues. Additionally, silencing E2F5 was able to inhibit the proliferation, colony formation, migration and invasion of ovarian cancer cells, parallel to the effect of miR-132 overexpression on the ovarian cancer cells. Meanwhile, overexpression of E2F5 reversed the inhibition effect mediated by miR-132 overexpression. These results indicate that miR-132 suppresses the cell proliferation, invasion, migration in ovarian cancer cells by targeting E2F5. PMID:27186275

  4. Targeting Serous Epithelial Ovarian Cancer with Designer Zinc Finger Transcription Factors*

    PubMed Central

    Lara, Haydee; Wang, Yuhua; Beltran, Adriana S.; Juárez-Moreno, Karla; Yuan, Xinni; Kato, Sumie; Leisewitz, Andrea V.; Cuello Fredes, Mauricio; Licea, Alexei F.; Connolly, Denise C.; Huang, Leaf; Blancafort, Pilar

    2012-01-01

    Ovarian cancer is the leading cause of death among gynecological malignancies. It is detected at late stages when the disease is spread through the abdominal cavity in a condition known as peritoneal carcinomatosis. Thus, there is an urgent need to develop novel therapeutic interventions to target advanced stages of ovarian cancer. Mammary serine protease inhibitor (Maspin) represents an important metastasis suppressor initially identified in breast cancer. Herein we have generated a sequence-specific zinc finger artificial transcription factor (ATF) to up-regulate the Maspin promoter in aggressive ovarian cancer cell lines and to interrogate the therapeutic potential of Maspin in ovarian cancer. We found that although Maspin was expressed in some primary ovarian tumors, the promoter was epigenetically silenced in cell lines derived from ascites. Transduction of the ATF in MOVCAR 5009 cells derived from ascitic cultures of a TgMISIIR-TAg mouse model of ovarian cancer resulted in tumor cell growth inhibition, impaired cell invasion, and severe disruption of actin cytoskeleton. Systemic delivery of lipid-protamine-RNA nanoparticles encapsulating a chemically modified ATF mRNA resulted in inhibition of ovarian cancer cell growth in nude mice accompanied with Maspin re-expression in the treated tumors. Gene expression microarrays of ATF-transduced cells revealed an exceptional specificity for the Maspin promoter. These analyses identified novel targets co-regulated with Maspin in human short-term cultures derived from ascites, such as TSPAN12, that could mediate the anti-metastatic phenotype of the ATF. Our work outlined the first targeted, non-viral delivery of ATFs into tumors with potential clinical applications for metastatic ovarian cancers. PMID:22782891

  5. Mathematical models of breast and ovarian cancers.

    PubMed

    Botesteanu, Dana-Adriana; Lipkowitz, Stanley; Lee, Jung-Min; Levy, Doron

    2016-07-01

    Women constitute the majority of the aging United States (US) population, and this has substantial implications on cancer population patterns and management practices. Breast cancer is the most common women's malignancy, while ovarian cancer is the most fatal gynecological malignancy in the US. In this review, we focus on these subsets of women's cancers, seen more commonly in postmenopausal and elderly women. In order to systematically investigate the complexity of cancer progression and response to treatment in breast and ovarian malignancies, we assert that integrated mathematical modeling frameworks viewed from a systems biology perspective are needed. Such integrated frameworks could offer innovative contributions to the clinical women's cancers community, as answers to clinical questions cannot always be reached with contemporary clinical and experimental tools. Here, we recapitulate clinically known data regarding the progression and treatment of the breast and ovarian cancers. We compare and contrast the two malignancies whenever possible in order to emphasize areas where substantial contributions could be made by clinically inspired and validated mathematical modeling. We show how current paradigms in the mathematical oncology community focusing on the two malignancies do not make comprehensive use of, nor substantially reflect existing clinical data, and we highlight the modeling areas in most critical need of clinical data integration. We emphasize that the primary goal of any mathematical study of women's cancers should be to address clinically relevant questions. WIREs Syst Biol Med 2016, 8:337-362. doi: 10.1002/wsbm.1343 For further resources related to this article, please visit the WIREs website. PMID:27259061

  6. Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer

    PubMed Central

    Guo, Hui; Zhong, Yan; Jackson, Amanda L.; Clark, Leslie H.; Kilgore, Josh; Zhang, Lu; Han, Jianjun; Sheng, Xiugui; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae, Victoria L.

    2016-01-01

    Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers. PMID:26959121

  7. Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention

    MedlinePlus

    ... lifestyle or eating habits. Avoiding things known to cause cancer. Taking medicines to treat a precancerous condition or ... called the endometrium. Ovarian cancer is the leading cause of death from cancer of the female reproductive system. In recent years, ...

  8. NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines.

    PubMed

    North, William G; Liu, Fuli; Tian, Ruiyang; Abbasi, Hamza; Akerman, Bonnie

    2015-01-01

    We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B. These specimens comprised malignant tissue with pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid adenocarcinoma, and clear-cell carcinoma. Additionally, archival tissues defined as ovarian adenocarcinoma from ten patients treated at this institute were also evaluated. All of the cancerous tissues demonstrated positive staining patterns with the NMDA-receptor antibodies, while no staining was found for tumor-adjacent normal tissues or sections of normal ovarian tissue. Human ovarian adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to express GluN1 by Western blotting, but displayed different levels of expression. Through immunocytochemistry utilizing GluN1 antibodies and imaging using a confocal microscope, we were able to demonstrate that GluN1 protein is expressed on the surface of these cells. In addition to these findings, GluN2B protein was demonstrated to be expressed using polyclonal antibodies against this protein. Treatment of all ovarian cell lines with antibodies against GluN1 was found to result in decreased cell viability (P<0.001), with decreases to 10%-25% that of untreated cells. Treatment of control HEK293 cells with various dilutions of GluN1 antibodies had no effect on cell viability. The GluN1 antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist ifenprodil, like antibodies, dramatically decreased the viability of A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor xenografts with

  9. NMDA receptors are expressed in human ovarian cancer tissues and human ovarian cancer cell lines

    PubMed Central

    North, William G; Liu, Fuli; Tian, Ruiyang; Abbasi, Hamza; Akerman, Bonnie

    2015-01-01

    We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B. These specimens comprised malignant tissue with pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid adenocarcinoma, and clear-cell carcinoma. Additionally, archival tissues defined as ovarian adenocarcinoma from ten patients treated at this institute were also evaluated. All of the cancerous tissues demonstrated positive staining patterns with the NMDA-receptor antibodies, while no staining was found for tumor-adjacent normal tissues or sections of normal ovarian tissue. Human ovarian adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to express GluN1 by Western blotting, but displayed different levels of expression. Through immunocytochemistry utilizing GluN1 antibodies and imaging using a confocal microscope, we were able to demonstrate that GluN1 protein is expressed on the surface of these cells. In addition to these findings, GluN2B protein was demonstrated to be expressed using polyclonal antibodies against this protein. Treatment of all ovarian cell lines with antibodies against GluN1 was found to result in decreased cell viability (P<0.001), with decreases to 10%–25% that of untreated cells. Treatment of control HEK293 cells with various dilutions of GluN1 antibodies had no effect on cell viability. The GluN1 antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist ifenprodil, like antibodies, dramatically decreased the viability of A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor xenografts with

  10. Targeting the tumour microenvironment in ovarian cancer.

    PubMed

    Hansen, Jean M; Coleman, Robert L; Sood, Anil K

    2016-03-01

    The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. PMID:26849037

  11. The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 1: olaparib.

    PubMed

    Miller, Rowan E; Ledermann, Jonathan A

    2016-08-01

    Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promising clinical activity in epithelial ovarian cancer. Following the observation in vitro that PARP inhibition is synthetically lethal in tumors with BRCA mutations, PARP inhibition has become the first genotype-directed therapy for BRCA1- and BRCA2-associated ovarian cancer. However, it is becoming clear that PARP inhibition also may have clinical utility in cancers associated with defects or aberrations in DNA repair that are unrelated to BRCA mutations. Deficient DNA repair mechanisms are present in approximately 30% to 50% of high-grade serous ovarian cancers, the most common histologic subtype. Olaparib is the best-studied PARP inhibitor to date, and a number of phase 3 trials with this agent are underway. This article reviews the development of olaparib for ovarian cancer and discusses the current evidence for its use, ongoing studies, future research directions, and the challenges ahead. PMID:27487106

  12. Ovarian cysts and cancer in pregnancy.

    PubMed

    Mukhopadhyay, Asima; Shinde, Aditi; Naik, Raj

    2016-05-01

    Adnexal masses are diagnosed in 5% pregnancies and pose diagnostic and management challenges. Ultrasound and magnetic resonance imaging (MRI) are the mainstay as an evaluation procedure; surgery is warranted for persistent masses with a diameter of >5 cm and sonographic signs of possible malignancy. Optimal timing for a planned surgery is the second trimester and does not adversely affect neonatal outcome. Laparoscopy is safe in pregnancy. Management for ovarian cancer during pregnancy should be individualised and formulated by a multidisciplinary team in a specialised centre while also considering the patients' wishes to preserve pregnancy. The following options can be considered: (i) induced abortion followed by standard management of ovarian cancer, (ii) pregnancy-preserving surgery followed by chemotherapy, planned delivery and secondary surgical completion or (iii) neoadjuvant chemotherapy followed by surgery during the postpartum period. Standard chemotherapy administered in non-pregnant population can only be used during the first trimester of pregnancy. PMID:26707193

  13. Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

    PubMed Central

    ZHANG, HONGMEI; ZHANG, LUOSHENG; WEI, LIXIA; GAO, XINGWANG; TANG, LI; GONG, WEI; MIN, NA; ZHANG, LI; YUAN, YAWEI

    2016-01-01

    Ovarian cancer is a leading gynecological malignancy associated with high mortality. The development of acquired drug resistance is the primary cause of chemotherapy failure in the treatment of ovarian cancer. To examine the mechanism underlying paclitaxel resistance in ovarian cancer and attempt to reverse it, the present study induced a TAX-resistant ovarian cancer cell line, SKOV3/TAX. Cathepsin L (CTSL) has been found to be overexpressed in ovarian cancer. The aim of the present study was to investigate the possible involvement of CTSL in the development of TAX resistance in ovarian cancer. CTSL expression was knocked down in SKOV3 ovarian cancer cells and their phenotypic changes were analyzed. The effects of silenced CTSL on the resistant cell line were investigated by proliferation and apoptosis analysis compared with control SKOV3 cells. CTSL was more highly expressed in SKOV3/TAX cells compared with SKOV3 cells. Paclitaxel treatment downregulated the expression of CTSL in SKOV-3 but not in the paclitaxel-resistant SKOV3/TAX cells. CTSL small hairpin RNA (shRNA) knockdown significantly potentiated apoptosis induced by paclitaxel compared with SKOV3/TAX cells transfected with control shRNA, suggesting that CTSL contributes to paclitaxel resistance in ovarian cancer cells and that CTSL silencing can enhance paclitaxel-mediated cell apoptosis. Thus, CTSL should be explored as a candidate of therapeutic target for modulating paclitaxel sensitivity in ovarian cancer. PMID:27313771

  14. Transcriptional regulation of chemokine expression in ovarian cancer.

    PubMed

    Singha, Bipradeb; Gatla, Himavanth R; Vancurova, Ivana

    2015-01-01

    The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies. PMID:25790431

  15. MiR-125a regulates ovarian cancer proliferation and invasion by repressing GALNT14 expression.

    PubMed

    Yang, Juan; Li, Guiyuan; Zhang, Keqiang

    2016-05-01

    Increasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to tumor progression. The miR-125a was downregulated in several types of cancer, however, the molecular mechanism of miR-125a in the ovarian cancer remains unclear. The aim of the paper was to reveal the mechanism of miR-125a regulating cell proliferation and metastasis in ovarian cancer. In this study, western blotting, immunohistochemistry and serum-ELISA assay revealed that polypeptide N-acetylgalactosaminyl transferase 14 (GALNT14) expression was upregulated and correlated with the cancer stage in ovarian cancer. The expression levels of miR-125a were downregulated and negatively related to GALNT14 expression in clinical ovarian cancer tissues. Moreover, luciferase reporter assay identified polypeptide N-acetylgalactosaminyl transferase 14 (GALNT14) as a direct target of miR-125a, and overexpression of miR-125a markedly reduced the expression of GALNT14 in ovarian cancer. Functional characterization of miR-125a was accomplished by reconstitution of miR-125a and silencing GALNT14 expression in ovarian cancer cells to determine changes in proliferation and invasion. The MTT assay and transwell assay revealed that miR-125a transfectant significantly inhibits cell proliferation and invasion, by repressing GALNT14 expression. Furthermore, the gelatin zymography assay miR-125a mimics and GALNT14 siRNA suppressed the activity of MMP2 and MMP9. Taken together, our findings show that miR-125a functions as tumor suppressor in ovarian cancer by targeting GALNT14, and miR-125a may therefore serve as a biomarker for diagnosis and therapeutics in ovarian cancer. PMID:27133078

  16. Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer

    PubMed Central

    Landen, Charles N.; Goodman, Blake; Katre, Ashwini A.; Steg, Adam D.; Nick, Alpa M.; Stone, Rebecca L.; Miller, Lance D.; Mejia, Pablo Vivas; Jennings, Nicolas B.; Gershenson, David M.; Bast, Robert C.; Coleman, Robert L.; Lopez-Berestein, Gabriel; Sood, Anil K.

    2010-01-01

    Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression, in whom the percent of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 v 13.81 months, p<0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared to chemotherapy alone (a 74–90% reduction, p<0.015). These data demonstrate that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity, but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer. PMID:20889728

  17. Sirolimus and Vaccine Therapy in Treating Patients With Stage II-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-08-15

    Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  18. Three-photon imaging of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Barton, Jennifer K.; Amirsolaimani, Babak; Rice, Photini; Hatch, Kenneth; Kieu, Khanh

    2016-02-01

    Optical imaging methods have the potential to detect ovarian cancer at an early, curable stage. Optical imaging has the disadvantage that high resolution techniques require access to the tissue of interest, but miniature endoscopes that traverse the natural orifice of the reproductive tract, or access the ovaries and fallopian tubes through a small incision in the vagina wall, can provide a minimally-invasive solution. We have imaged both rodent and human ovaries and fallopian tubes with a variety of endoscope-compatible modalities. The recent development of fiber-coupled femtosecond lasers will enable endoscopic multiphoton microscopy (MPM). We demonstrated two- and three-photon excited fluorescence (2PEF, 3PEF), and second- and third-harmonic generation microscopy (SHG, THG) in human ovarian and fallopian tube tissue. A study was undertaken to understand the mechanisms of contrast in these images. Six patients (normal, cystadenoma, and ovarian adenocarcinoma) provided ovarian and fallopian tube biopsies. The tissue was imaged with three-dimensional optical coherence tomography, multiphoton microscopy, and frozen for histological sectioning. Tissue sections were stained with hematoxylin and eosin, Masson's trichrome, and Sudan black. Approximately 1 μm resolution images were obtained with an excitation source at 1550 nm. 2PEF signal was absent. SHG signal was mainly from collagen. 3PEF and THG signal came from a variety of sources, including a strong signal from fatty connective tissue and red blood cells. Adenocarcinoma was characterized by loss of SHG signal, whereas cystic abnormalities showed strong SHG. There was limited overlap of two- and three- photon signals, suggesting that three-photon imaging can provide additional information for early diagnosis of ovarian cancer.

  19. Salpingectomy as a Means to Reduce Ovarian Cancer Risk

    PubMed Central

    Daly, Mary B.; Dresher, Charles W.; Yates, Melinda S.; Jeter, Joanne M.; Karlan, Beth Y.; Alberts, David S.; Lu, Karen H.

    2015-01-01

    Bilateral salpingo-oophorectomy (BSO) has become the standard of care for risk reduction in women at hereditary risk of ovarian cancer. While this procedure significantly decreases both the incidence of and mortality from ovarian cancer, it impacts quality of life, and the premature cessation of ovarian function may have long term health hazards. Recent advances in our understanding of the molecular pathways of ovarian cancer point to the fallopian tube epithelium as the origin of most high grade serous cancers (HGSC). This evolving appreciation of the role of the fallopian tube in HGSC has led to the consideration of salpingectomy alone as an option for risk management, especially in premenopausal women. In addition, it is postulated that bilateral salpingectomy with ovarian retention (BSOR), may have a public health benefit for women undergoing benign gynecologic surgery. In this review we provide the rationale for salpingectomy as an ovarian cancer risk reduction strategy. PMID:25586903

  20. MicroRNAs and Recent Insights into Pediatric Ovarian Cancers

    PubMed Central

    Francis, Jessica C.; Kolomeyevskaya, Nonna; Mach, Claire M.; Dietrich, Jennifer E.; Anderson, Matthew L.

    2013-01-01

    Ovarian cancer is the most common pediatric gynecologic malignancy. When diagnosed in children, ovarian cancers present unique challenges that differ dramatically from those faced by adults. Here, we review the spectrum of ovarian cancers found in young women and girls and discuss the biology of these diseases. A number of advances have recently shed significant new understanding on the potential causes of ovarian cancer in this unique population. Particular emphasis is placed on understanding how altered expression of non-coding RNA transcripts known as microRNAs play a key role in the etiology of ovarian germ cell and sex cord-stromal tumors. Emerging transgenic models for these diseases are also reviewed. Lastly, future challenges and opportunities for understanding pediatric ovarian cancers, delineating clinically useful biomarkers, and developing targeted therapies are discussed. PMID:23641362

  1. Ovarian Cancer Biomarker Discovery Based on Genomic Approaches

    PubMed Central

    Lee, Jung-Yun; Kim, Hee Seung; Suh, Dong Hoon; Kim, Mi-Kyung; Chung, Hyun Hoon; Song, Yong-Sang

    2013-01-01

    Ovarian cancer presents at an advanced stage in more than 75% of patients. Early detection has great promise to improve clinical outcomes. Although the advancing proteomic technologies led to the discovery of numerous ovarian cancer biomarkers, no screening method has been recommended for early detection of ovarian cancer. Complexity and heterogeneity of ovarian carcinogenesis is a major obstacle to discover biomarkers. As cancer arises due to accumulation of genetic change, understanding the close connection between genetic changes and ovarian carcinogenesis would provide the opportunity to find novel gene-level ovarian cancer biomarkers. In this review, we summarize the various gene-based biomarkers by genomic technologies, including inherited gene mutations, epigenetic changes, and differential gene expression. In addition, we suggest the strategy to discover novel gene-based biomarkers with recently introduced next generation sequencing. PMID:25337559

  2. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells.

    PubMed

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12-24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  3. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells

    PubMed Central

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K.; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C.; Luu, Hue H.; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12–24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  4. Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer

    PubMed Central

    Tsai, Hsiang-Ping; An, Herng-Wei; Lee, Chi-Ming; Wu, Jen-Chine; Chen, Chien-Shu; Huang, Shih-Hao; Hwang, Jaulang; Cheng, Kur-Ta; Leiw, Phui-Ly; Chen, Chi-Long; Lin, Chun-Mao

    2015-01-01

    DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p < 0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers. PMID:26207989

  5. Metformin Hydrochloride and Combination Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-05-18

    Brenner Tumor; Malignant Ascites; Malignant Pleural Effusion; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Primary Peritoneal Cavity Cancer

  6. Clinical tumour markers in ovarian cancer.

    PubMed

    Mazurek, A; Nikliński, J; Laudański, T; Pluygers, E

    1998-02-01

    Within past few years, the measurement of serological, histochemical and molecular genetic markers has had an increasing influence on clinical decisions about initial treatment and follow-up. This review presents data concerning the most studied and interesting markers in ovarian cancer. CA 125, CA 19.9, TATI, CASA, CEA, TPA, TPS and CYFRA21-1 are now the most widely used serological tumour markers for management of ovarian cancer patients. Ras oncogenes, C-erb2 proto-oncogene, p53 suppressor gene and Bcl-2 oncogene are examples of currently used molecular genetic markers. As histochemical markers-proliferation markers, flow cytometric analysis, thymidine labelling index, Ki-67 nuclear antigen or differentiation markers are nowadays the ones most often determined. Some of these markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure. The study of these markers may also lead to a better understanding of the biological characteristics of ovarian cancer. Numerous tumour markers characterized in this paper have been recognized as promising prognostic factors. The information derived from studies of these markers also represents the most promising avenue towards new treatment strategies; nevertheless to validate these factors, prospective studies of a large patient population are needed. PMID:9511849

  7. Concomitant BET and MAPK blockade for effective treatment of ovarian cancer

    PubMed Central

    An, Shimin; Shen, Ying; Zhu, Liang; Zhuang, Guanglei

    2016-01-01

    Ovarian cancer is the most lethal gynecologic malignancy, and it is imperative to develop new treatments to ameliorate patient survival. Using an anti-cancer drug library containing 180 small molecule inhibitors, we performed a high-content image-based screen and found that BET and MEK inhibitors are among the candidates which were able to effectively inhibit ovarian cancer cell growth. However, BET inhibition alone was largely cytostatic, possibly due to feedback activation of the MAPK pathway. Consequently, the combination of MEK and BET inhibitors suppressed both cell proliferation and survival, and was more efficacious than single agent. Mechanistically, BET and MEK inhibitors exerted synergistic effects on apoptosis regulators including BIM and BAD. Our findings support concomitant BET and MAPK blockade as an effective therapeutic strategy in ovarian cancer. PMID:26575423

  8. [Hope for improvement of survival in ovarian cancer].

    PubMed

    Högberg, Thomas; Bergfeldt, Kjell; Borgfeldt, Christer; Holmberg, Erik; Åvall Lundqvist, Elisabeth

    2015-01-01

    Ovarian cancer is the most common cause of death from a gynecologic cancer. Every year around 700 women contracts ovarian cancer in Sweden. The overall survival is among the highest in Europe, but still long term relative survival is only 46%. It is a long-held myth that ovarian cancer is a disease without symptoms. Almost 90% of women have symptoms, even in the early stages. Symptoms that should arise suspicion of ovarian cancer and initiate diagnostic work-up are continuous abdominal extension, early feeling of satiety, pelvic or abdominal pain, urinary urge and postmenopausal bleeding. Women's awareness of symptoms and willingness to seek medical advice and the organization of the health care system are important factors determining cancer survival. Ovarian cancer is a heterogeneous group of diseases with different tumor traits and prognosis. Personalized medicine and preventive measures recognizing recent knowledge about tumor biology will positively affect survival. PMID:26646961

  9. Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer

    PubMed Central

    Zhu, Xiu-Jie; Lin, Feng; Pan, Shi-Shi; Gong, Li-Hua; Qiu, Jian-Ge; Zhang, Wen-Ji; Jiang, Qi-Wei; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Shi, Zhi; Yan, Xiao-Jian

    2015-01-01

    Ovarian cancer is one of the most lethal of woman cancers, and its clinical therapeutic outcome currently is unsatisfied. Dinaciclib, a novel small molecule inhibitor of CDK1, CDK2, CDK5 and CDK9, is assessed in clinical trials for the treatment of several types of cancers. In this study, we investigated the anticancer effects and mechanisms of dinaciclib alone or combined with cisplatin in ovarian cancer. Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin. Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib. Moreover, the combination of dinaciclib with cisplatin synergistically promoted cell cycle arrest and apoptosis, and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer. PMID:25962959

  10. The role of hormonal factors and endocrine therapy in ovarian cancer

    PubMed Central

    Sinacki, Marcin; Jassem, Jacek

    2013-01-01

    The efficacy of the second-line chemotherapy commonly used in both relapsed ovarian cancer patients and those with primary treatment failure remains unsatisfactory. This therapy has a small effect on survival, whereas associated toxicity may diminish the patient's quality of life. Hormonal factors play a role in ovarian tumorigenesis, and inhibition of the stimulating effects of estrogens may exert a clinical benefit. The role of hormonal therapy as a palliative therapeutic alternative for ovarian cancer remains undetermined. This modality may result in long-term stabilization of disease in individual patients and less frequently in tumor remission. In this article the role of hormonal factors and recent literature of various forms of hormonal therapy for ovarian cancer are presented. PMID:23788955

  11. Management of relapsed ovarian cancer: a review.

    PubMed

    Giornelli, Gonzalo H

    2016-01-01

    Around 70 % of ovarian cancer patients relapse after primary cytoreductive surgery and standard first-line chemotherapy. The biology of relapse remains unclear, but cancer stem cells seem to play an important role. There are still some areas of controversy on how to manage these relapses and or progressions that occur almost unavoidably in the course of this disease with shorter intervals between them as the natural history of this disease develops. The goal of treatments investigated in this neoplasm has shifted to maintenance therapy, trying to extend the progression free intervals in a disease that is becoming more and more protracted. PMID:27516935

  12. Noncontraceptive estrogen use and epithelial ovarian cancer.

    PubMed

    Kaufman, D W; Kelly, J P; Welch, W R; Rosenberg, L; Stolley, P D; Warshauer, M E; Lewis, J; Woodruff, J; Shapiro, S

    1989-12-01

    The relation of noncontraceptive estrogen use to epithelial ovarian cancer was evaluated in a case-control study conducted in hospitals mainly in the northeastern United States. There were 377 cases diagnosed within the year before hospital admission and 2,030 hospital controls; data were collected by interview in the hospital. Compared with women who never took noncontraceptive estrogens, the overall relative risk estimate for women whose estrogen use lasted at least one year and was not combined with progestogens or testosterone was 1.2 (95% confidence interval (CI) 0.8-1.9), after taking into account risk factors for ovarian cancer. There were 55 cases of the endometrioid, clear cell, or malignant mixed mesodermal cell type; the corresponding relative risk estimate was 0.9 (95% CI 0.3-3.0). There were 26 cases of undifferentiated cell type, with a relative risk estimate of 3.6 (95% CI 1.2-11). Relative risk estimates were similar in a subset of the cases (57%) for which pathology slides were reviewed. For estrogen use of long duration, use of high-dose preparations, or use in the distant past, the relative risk estimates were not significantly different from 1.0. The estimates were elevated for some categories of use, but not consistently--for example, for an interval of 5-9 years since estrogen use began (relative risk (RR) = 2.7), but not after shorter or longer intervals, and for use of conjugated estrogens with a dose of 0.3 mg (RR = 3.2) or 1.25 mg (RR = 2.4), but not for doses of 0.625 mg or 2.5 mg. The relative risk estimate was also elevated for use by nulliparous women (RR = 2.4). The results suggest that, overall, noncontraceptive estrogen use is not associated with the risk of epithelial ovarian cancer. Furthermore, our data do not support the hypothesis that estrogens increase the risk of endometrioid ovarian cancer. The elevated estimates could be due to multiple stratification of the data, but they should be explored in further studies, given the

  13. Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer.

    PubMed

    He, X; Arslan, A D; Pool, M D; Ho, T-T; Darcy, K M; Coon, J S; Beck, W T

    2011-01-20

    Our previous study revealed that two splicing factors, polypyrimidine tract-binding protein (PTB) and SRp20, were upregulated in epithelial ovarian cancer (EOC) and knockdown of PTB expression inhibited ovarian tumor cell growth and transformation properties. In this report, we show that knockdown of SRp20 expression in ovarian cancer cells also causes substantial inhibition of tumor cell growth and colony formation in soft agar and the extent of such inhibition appeared to correlate with the extent of suppression of SRp20. Massive knockdown of SRp20 expression triggered remarkable apoptosis in these cells. These results suggest that overexpression of SRp20 is required for ovarian tumor cell growth and survival. Immunohistochemical staining for PTB and SRp20 of two specialized tissue microarrays, one containing benign ovarian tumors, borderline/low malignant potential (LMP) ovarian tumors as well as invasive EOC and the other containing invasive EOC ranging from stage I to stage IV disease, reveals that PTB and SRp20 are both expressed differentially between benign tumors and invasive EOC, and between borderline/LMP tumors and invasive EOC. There were more all-negative or mixed staining cases (at least two evaluable section cores per case) in benign tumors than in invasive EOC, whereas there were more all-positive staining cases in invasive EOC than in the other two disease classifications. Among invasive EOC, the majority of cases were stained all positive for both PTB and SRp20, and there were no significant differences in average staining or frequency of positive cancer cells between any of the tumor stages. Therefore, the expression of PTB and SRp20 is associated with malignancy of ovarian tumors but not with stage of invasive EOC. PMID:20856201

  14. Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer

    PubMed Central

    He, Xiaolong; Arslan, Ahmet Dirim; Pool, Mark D.; Ho, Tsui-Ting; Darcy, Kathleen M.; Coon, John S.; Beck, William T.

    2010-01-01

    Our previous study revealed that two splicing factors, polypyrimidine tract-binding protein (PTB) and SRp20, were up-regulated in epithelial ovarian cancer (EOC) and knockdown of PTB expression inhibited ovarian tumor cell growth and transformation properties. In this report, we show that knockdown of SRp20 expression in ovarian cancer cells also causes substantial inhibition of tumor cell growth and colony formation in soft agar and the extent of such inhibition appeared to correlate with the extent of suppression of SRp20. Massive knockdown of SRp20 expression triggered remarkable apoptosis in these cells. These results suggest that overexpression of SRp20 is required for ovarian tumor cell growth and survival. Immunohistochemical staining for PTB and SRp20 of two specialized tissue microarrays (TMAs), one containing benign ovarian tumors, borderline/low malignant potential (LMP) ovarian tumors as well as invasive EOC and the other containing invasive EOC ranging from stage I to stage IV disease, reveals that PTB and SRp20 are both expressed differentially between benign tumors and invasive EOC, and between borderline/LMP tumors and invasive EOC. There were more all-negative or mixed staining cases (at least two evaluable section cores per case) in benign tumors than in invasive EOC while there were more all positive staining cases in invasive EOC than in the other two disease classifications. Among invasive EOC, the great majority of cases were stained all-positive for both PTB and SRp20 and there were no significant differences in average staining or frequency of positive cancer cells between any of the tumor stages. Therefore, the expression of PTB and SRp20 is associated with malignancy of ovarian tumors but not with stage of invasive EOC. PMID:20856201

  15. Tumor microenvironment: The culprit for ovarian cancer metastasis?

    PubMed

    Luo, Zhongyue; Wang, Qiu; Lau, Wayne Bond; Lau, Bonnie; Xu, Lian; Zhao, Linjie; Yang, Huiliang; Feng, Min; Xuan, Yu; Yang, Yanfei; Lei, Lingzi; Wang, Chenlu; Yi, Tao; Zhao, Xia; Wei, Yuquan; Zhou, Shengtao

    2016-07-28

    Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently, with poor prognosis. However, the molecular mechanisms underlying ovarian cancer metastasis still remain unelucidated. The tumor microenvironment, consisting of stromal cells (including fibroblasts, macrophages, regulatory T cells, myeloid-derived suppressor cells, endothelial cells, pericytes and platelets), the extracellular matrix component (EMC) (including inflammatory cytokines, chemokines, matrix metalloproteinases, integrins, and other secreted molecules) and exosomes (small extracellular vesicles loaded with molecules), establishes an autocrine-paracrine communication circuit that reinforces invasion and cancer cell metastasis via reciprocal signaling. Recent evidences have unraveled the significant contribution of tumor microenvironment to ovarian cancer metastasis. In this review, we provide a comprehensive landscape of the reciprocity between tumor stroma and ovarian cancer cells upon metastasis, aiming to offer novel clues on the development of novel diagnostic biomarkers and therapeutic targets for ovarian cancer in future clinical practice. PMID:27131957

  16. Development of a Mouse Model of Menopausal Ovarian Cancer

    PubMed Central

    Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

    2014-01-01

    Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

  17. KRAS genomic status predicts the sensitivity of ovarian cancer cells to decitabine

    PubMed Central

    Stewart, ML; Tamayo, P; Wilson, AJ; Wang, S; Chang, YM; Kim, JW; Khabele, D; Shamji, AF; Schreiber, SL

    2015-01-01

    Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low and high-grade serous ovarian cancer cells. Pre-treatment with decitabine decreased the cytotoxic activity of MEK inhibitors in KRAS-mutant ovarian cancer cells, with reciprocal downregulation of DNMT1 and MEK/ERK phosphorylation. In parallel with these responses, decitabine also upregulated the pro-apoptotic BCL-2 family member BNIP3, which is known to be regulated by MEK and ERK, and heightened the activity of pro-apoptotic small molecule navitoclax, a BCL-2 family inhibitor. In a xenograft model of KRAS-mutant ovarian cancer, combining decitabine and navitoclax heighted antitumor activity beyond administration of either compound alone. Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition, specifically implicating KRAS status as a biomarker of drug response in ovarian cancer. PMID:25968887

  18. Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

    PubMed Central

    Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna

    2011-01-01

    Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute

  19. 78 FR 54741 - National Ovarian Cancer Awareness Month, 2013

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-06

    ... America the two hundred and thirty- eighth. (Presidential Sig.) [FR Doc. 2013-21821 Filed 9-5-13; 8:45 am... Documents#0;#0; ] Proclamation 9008 of August 30, 2013 National Ovarian Cancer Awareness Month, 2013 By the... ovarian cancer, and more than half that number of women will die of this disease. During National...

  20. 77 FR 55095 - National Ovarian Cancer Awareness Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-06

    .... (Presidential Sig.) [FR Doc. 2012-22148 Filed 9-5-12; 11:15 am] Billing code 3295-F2-P ... Documents#0;#0; ] Proclamation 8853 of August 31, 2012 National Ovarian Cancer Awareness Month, 2012 By the... their lives to ovarian cancer. They are mothers and daughters, sisters and grandmothers,...

  1. [Tardive cecal metastasis from ovarian cancer: a case report].

    PubMed

    Talarico, C; Casella, C; Gambarotti, M

    2004-01-01

    Intestinal insolvement is a frequent sequela of metastatic ovarian cancer may be syncronous or following ovaric resection, after several years of disease free condition. The authors herein describe a clinical report of a case of cecal metastatic neoplasm due to ovarian cancer treated with surgical resection 24 years before. PMID:15960367

  2. Recreational Physical Activity and Ovarian Cancer Risk and Survival

    PubMed Central

    Moorman, Patricia G.; Jones, Lee W.; Akushevich, Lucy; Schildkraut, Joellen M.

    2010-01-01

    Purpose Physical activity may influence ovarian cancer risk and outcomes through effects on ovulation, inflammatory markers and other processes. We examined associations between self-reported physical activity and ovarian cancer risk and survival in a population-based, case-control study in North Carolina. Methods The analyses involved 638 epithelial ovarian cancer cases and 683 controls recruited between 1999-2008. Logistic regression analyses were used to assess ovarian cancer risk in relation to reported average physical activity at various time periods. Kaplan-Meier analyses and proportional hazards modeling were used to assess associations between physical activity and survival among ovarian cancer cases. Results Modestly reduced risks for ovarian cancer were observed in some categories of physical activity, but there were no consistent patterns of greater reductions in risk with higher activity levels. Physical activity prior to diagnosis was not significantly related to ovarian cancer survival overall, but survival was better for women who reported >2 hours of activity/week as compared to those reporting <1 hour/week among women who were non-obese (multivariable hazard ratio=0.69, 95% CI 0.47 – 1.00) Conclusions Our data provide weak evidence in support of beneficial effects of physical activity on ovarian cancer risk and survival, but results should be interpreted cautiously because of the lack of a clear dose response relation with higher levels of exercise and the likely misclassification of self-reported activity. PMID:21296269

  3. 75 FR 54451 - National Ovarian Cancer Awareness Month, 2010

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-07

    .... (Presidential Sig.) [FR Doc. 2010-22427 Filed 9-3-10; 11:15 am] Billing code 3195-W0-P ... Documents#0;#0; ] Proclamation 8551 of August 31, 2010 National Ovarian Cancer Awareness Month, 2010 By the... against ovarian cancer, this disease continues to claim more lives than any other gynecologic...

  4. Risk of Ovarian Cancer Relapse Score

    PubMed Central

    Rizzuto, Ivana; Stavraka, Chara; Chatterjee, Jayanta; Borley, Jane; Hopkins, Thomas Glass; Gabra, Hani; Ghaem-Maghami, Sadaf; Huson, Les; Blagden, Sarah P.

    2015-01-01

    Objective The aim of this study was to construct a prognostic index that predicts risk of relapse in women who have completed first-line treatment for ovarian cancer (OC). Methods A database of OC cases from 2000 to 2010 was interrogated for International Federation of Gynecology and Obstetrics stage, grade and histological subtype of cancer, preoperative and posttreatment CA-125 level, presence or absence of residual disease after cytoreductive surgery and on postchemotherapy computed tomography scan, and time to progression and death. The strongest predictors of relapse were included into an algorithm, the Risk of Ovarian Cancer Relapse (ROVAR) score. Results Three hundred fifty-four cases of OC were analyzed to generate the ROVAR score. Factors selected were preoperative serum CA-125, International Federation of Gynecology and Obstetrics stage and grade of cancer, and presence of residual disease at posttreatment computed tomography scan. In the validation data set, the ROVAR score had a sensitivity and specificity of 94% and 61%, respectively. The concordance index for the validation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patient stratification into low (<0.33), intermediate (0.34–0.67), and high (>0.67) probability of relapse. Conclusions The ROVAR score stratifies patients according to their risk of relapse following first-line treatment for OC. This can broadly facilitate the appropriate tailoring of posttreatment care and support. PMID:25647256

  5. Inhibition of ovarian cancer cell proliferation in vivo and incorporation of /sup 3/H-thymidine in vitro after follicle regulatory protein administration

    SciTech Connect

    Rodgers, K.E.; Montz, F.J.; Scott, L.; Condon, S.; Fujimori, K.; diZerega, G.S.

    1989-01-01

    Follicle regulatory protein immunoreactivity and biologic activity were measured in ascites from a patient with juvenile granulosa cell tumor. Microscopic examination of immunohistochemical staining of a juvenile granulosa cell tumor with anti-follicle regulatory protein antisera showed homogeneous cytosolic expression of follicle regulatory protein throughout the tumor. Tumor cells were injected subcutaneously into nude mice. Partially purified follicle regulatory protein (50 micrograms/day) was then injected daily for 10 days, or for 25 days once the tumor became palpable. Treatment with follicle regulatory protein significantly slowed the rate of tumor growth with both treatments. To test the tissue specificity of the effect, a metastatic, well-differentiated endometrial adenocarcinoma was also grown in nude mice. Follicle regulatory protein treatment did not alter the rate of tumor growth. An in vitro clonigenic assay confirmed these in vivo results. Partially purified follicle regulatory protein had a biphasic effect on the proliferation of juvenile granulosa tumor cell but did not affect the proliferation of endometrial adenocarcinoma cells. Clonigenic assays were performed on five ovarian adenocarcinomas passaged in vitro, and these tumor cells exhibited a biphasic response to follicle regulatory protein. Immunoneutralization studies showed that this biphasic response was due to impurities in the follicle regulatory protein preparations. The longer the exposure of the tumor cells to follicle regulatory protein, the greater the degree of inhibition of proliferation. In summary, administration of follicle regulatory protein slowed tumor growth through a direct effect on the tumor cell rather than an indirect effect on the hormonal or immune status of the host.

  6. MiR-506 inhibits multiple targets in the epithelial-to-mesenchymal transition network and is associated with good prognosis in epithelial ovarian cancer

    PubMed Central

    Sun, Yan; Hu, Limei; Zheng, Hong; Bagnoli, Marina; Guo, Yuhong; Rupaimoole, Rajesha; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Ji, Ping; Chen, Kexin; Sood, Anil K.; Mezzanzanica, Delia; Liu, Jinsong; Sun, Baocun; Zhang, Wei

    2014-01-01

    Extensive investigations have shown that miRNAs are important regulators of epithelial-to-mesenchymal transition (EMT), mainly targeting the transcriptional repressors of E-cadherin (Ecad). Less is known about the post-transcriptional regulation of vimentin or N-cadherin (N-cad) in EMT. Our previous study identified miR-506 as a key EMT inhibitor through directly targeting the E-cad transcriptional repressor, SNAI2. In this study, we provide evidence that miR-506 simultaneously suppresses vimentin and N-cad. The knockdown of vimentin using siRNA reversed EMT, suppressed cell migration and invasion, and increased E-cad expression on cell membrane in epithelial ovarian cancer (EOC) cells. In a set of tissue microarrays that included 204 EOCs of all major subtypes (e.g., serous, endometrioid, clear cell, and mucinous), miR-506 was positively correlated with E-cad and negatively correlated with vimentin and N-cad in all subtypes of EOC. A high level of miR-506 was positively associated with early FIGO stage and longer survival in EOC. Introduction of miR-506, mediated by nanoparticle delivery, in EOC orthotopic mouse models resulted in decreased vimentin, N-cad, and SNAI2 expression and increased E-cad expression; it also suppressed the dissemination of EOC cells. Thus, miR-506 represents a new class of miRNA that regulates both E-cad and vimentin/N-cad in the suppression of EMT and metastasis. PMID:25230372

  7. Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

    SciTech Connect

    Zhan, Yu; Abi Saab, Widian F.; Modi, Nidhi; Stewart, Amanda M.; Liu, Jinsong; Chadee, Deborah N.

    2012-08-15

    Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. -- Highlights: Black-Right-Pointing-Pointer Ovarian cancer cell lines have high levels of total and phosphorylated MLK3. Black-Right-Pointing-Pointer MLK3 is required for MMP expression and activity in ovarian cancer cells. Black-Right-Pointing-Pointer MLK3 is required for invasion of SKOV3 and HEY1B ovarian cancer cells. Black-Right-Pointing-Pointer MLK3-dependent regulation of MMP-2 and MMP-9 activities requires ERK and JNK.

  8. General Information About Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

    MedlinePlus

    ... condition or to keep cancer from starting. General Information About Ovarian, Fallopian Tube, and Primary Peritoneal Cancer ... PDQ Screening and Prevention Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  9. Identification of therapeutic targets in ovarian cancer through active tyrosine kinase profiling

    PubMed Central

    Ocaña, Alberto; Pandiella, Atanasio

    2015-01-01

    The activation status of a set of pro-oncogenic tyrosine kinases in ovarian cancer patient samples was analyzed to define potential therapeutic targets. Frequent activation of HER family receptor tyrosine kinases, especially HER2, was observed. Studies in ovarian cancer cell lines confirmed the activation of HER2. Moreover, knockdown of HER2 caused a strong inhibition of their proliferation. Analyses of the action of agents that target HER2 indicated that the antibody drug conjugate trastuzumab-emtansine (T-DM1) caused a substantial antitumoral effect in vivo and in vitro, and potentiated the action of drugs used in the therapy of ovarian cancer. T-DM1 provoked cell cycle arrest in mitosis, and caused the appearance of aberrant mitotic spindles in cells treated with the drug. Biochemical experiments confirmed accumulation of the mitotic markers phospho-Histone H3 and phospho-BUBR1 in cells treated with the drug. Prolonged treatment of ovarian cancer cells with T-DM1 provoked the appearance of multinucleated cells which later led to cell death. Together, these data indicate that HER2 represents an important oncogene in ovarian cancer, and suggest that targeting this tyrosine kinase with T-DM1 may be therapeutically effective, especially in ovarian tumors with high content of HER2. PMID:26336133

  10. [Individualized therapy of synchronous ovarian and colon cancers with lymph].

    PubMed

    Deme, Dániel; Bishr, Abdulfatah M; Nizar, Jamool; Telekes, András

    2015-06-01

    A 71-year-old female patient underwent urgent laparotomy due to severe right lower quadrant abdominal pain and fever. Macroscopically duplex coecal and transverse colon cancer as well as a sigmoid or left ovarian cancer were suspected. Pathological findings revealed synchronous left ovarian and transverse colonic neoplasms. Both primaries metastatized to their regional lymph nodes. Furthermore, the ovarian cancer infiltrating the sigmoid colon gave distant metastasis in the coecum, too. Ovarian cancer histology showed papillary adenocarcinoma, and transverse colon cancer was a tubular adenocarcinoma. The affected lymph nodes were clearly distinguished by immunohistochemistry staining: ovarian metastases were CK7 positive, and colonic metastases were CK20 and CEA positive. The patient was treated with combinated chemotherapy: FOLFOX-4 two weekly and paclitaxel monotherapy every other week. The patient tolerated this combined treatment well. The authors conclude that multiple synchronous neoplasms can be treated with individualized chemotherapeutic protocol with good efficacy and few adverse reactions. PMID:26027602

  11. DNA methylation changes in epithelial ovarian cancer histotypes

    PubMed Central

    Earp, Madalene A.; Cunningham, Julie M.

    2016-01-01

    Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There’s considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field. PMID:26363302

  12. Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers

    PubMed Central

    Mehner, Christine; Oberg, Ann L.; Kalli, Kimberly R.; Nassar, Aziza; Hockla, Alexandra; Pendlebury, Devon; Cichon, Magdalena A.; Goergen, Krista M.; Maurer, Matthew J.; Goode, Ellen L.; Keeney, Gary L.; Jatoi, Aminah; Sahin-Tóth, Miklós; Copland, John A.; Radisky, Derek C.; Radisky, Evette S.

    2015-01-01

    Ovarian cancer represents the most lethal tumor type among malignancies of the female reproductive system. Overall survival rates remain low. In this study, we identify the serine protease inhibitor Kazal type 1 (SPINK1) as a potential therapeutic target for a subset of ovarian cancers. We show that SPINK1 drives ovarian cancer cell proliferation through activation of epidermal growth factor receptor (EGFR) signaling, and that SPINK1 promotes resistance to anoikis through a distinct mechanism involving protease inhibition. In analyses of ovarian tumor specimens from a Mayo Clinic cohort of 490 patients, we further find that SPINK1 immunostaining represents an independent prognostic factor for poor survival, with the strongest association in patients with nonserous histological tumor subtypes (endometrioid, clear cell, and mucinous). This study provides novel insight into the fundamental processes underlying ovarian cancer progression, and also suggests new avenues for development of molecularly targeted therapies. PMID:26437224

  13. Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells

    PubMed Central

    Scharer, Christopher D; Laycock, Noelani; Osunkoya, Adeboye O; Logani, Sanjay; McDonald, John F; Benigno, Benedict B; Moreno, Carlos S

    2008-01-01

    Background A large percentage of patients with recurrent ovarian cancer develop resistance to the taxane class of chemotherapeutics. While mechanisms of resistance are being discovered, novel treatment options and a better understanding of disease resistance are sorely needed. The mitotic kinase Aurora-A directly regulates cellular processes targeted by the taxanes and is overexpressed in several malignancies, including ovarian cancer. Recent data has shown that overexpression of Aurora-A can confer resistance to the taxane paclitaxel. Methods We used expression profiling of ovarian tumor samples to determine the most significantly overexpressed genes. In this study we sought to determine if chemical inhibition of the Aurora kinase family using VE-465 could synergize with paclitaxel to induce apoptosis in paclitaxel-resistant and sensitive ovarian cancer cells. Results Aurora-A kinase and TPX2, an activator of Aurora-A, are two of the most significantly overexpressed genes in ovarian carcinomas. We show that inhibition of the Aurora kinases prevents phosphorylation of a mitotic marker and demonstrate a dose-dependent increase of apoptosis in treated ovarian cancer cells. We demonstrate at low doses that are specific to Aurora-A, VE-465 synergizes with paclitaxel to induce 4.5-fold greater apoptosis than paclitaxel alone in 1A9 cells. Higher doses are needed to induce apoptosis in paclitaxel-resistant PTX10 cells. Conclusion Our results show that VE-465 is a potent killer of taxane resistant ovarian cancer cells and can synergize with paclitaxel at low doses. These data suggest patients whose tumors exhibit high Aurora-A expression may benefit from a combination therapy of taxanes and Aurora-A inhibition. PMID:19077237

  14. LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion.

    PubMed

    Li, Yuanxia; Wan, Xiaolei; Wei, Ye; Liu, Xiuwen; Lai, Wensheng; Zhang, Liuping; Jin, Jie; Wu, Chaoyang; Shao, Qixiang; Shao, Genbao; Lin, Qiong

    2016-06-01

    Lysine-specific demethylase 1 (LSD1) has been implicated in the process of tumor progression at various steps, but its role in epithelial-messenchymal transition (EMT) and the migration of ovarian cancer cells remains obscure. In this study, we demonstrated the effect of LSD1 on ovarian cancer cell migration and the regulatory role of LSD1 in the expression of EMT markers. Inhibition of LSD1 expression impaired the migration and invasion of HO8910 ovarian cancer cells. In contrast, overexpression of LSD1 enhanced the cell migration and invasion of HO8910 cells. Mechanistic analyses showed that LSD1 promoted cell migration through induction of N-cadherin, vimentin, MMP-2 and inhibition of E-cadherin. Furthermore, LSD1 interacted with the promoter of E-cadherin and demethylated histone H3 lysine 4 (H3K4) at this region, downregulated E-cadherin expression, and consequently enhanced ovarian cancer cell migration. These data indicate that LSD1 acts as an epigenetic regulator of EMT and contributes to the metastasis of ovarian cancer. PMID:27109588

  15. MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer.

    PubMed

    Xie, Suhong; Zheng, Hui; Wen, Xuemei; Sun, Jiajun; Wang, Yanchun; Gao, Xiang; Guo, Lin; Lu, Renquan

    2016-08-01

    The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis. Here, we observed that MUS81 was over-expressed in SOC tissues at both transcript and protein levels, and the expression level of MUS81 protein in ovarian cancer cell lines was also higher than that in human normal ovarian surface epithelial cell line (HOSEpiC). We also found that down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression. Moreover, inhibition of MUS81 expression induced cellular senescence and enhanced the antitumor effect of cisplatin. Down-regulation of MUS81 expression could suppress the growth and development of SOC. These results indicate that MUS81 might play important roles in the progression of SOC and influence the antitumor effect of cisplatin. PMID:27255997

  16. Short-form Ron is a novel determinant of ovarian cancer initiation and progression.

    PubMed

    Moxley, Katherine M; Wang, Luyao; Welm, Alana L; Bieniasz, Magdalena

    2016-05-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  17. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

    PubMed

    Secreto, Giorgio; Sieri, Sabina; Agnoli, Claudia; Grioni, Sara; Muti, Paola; Zumoff, Barnett; Sant, Milena; Meneghini, Elisabetta; Krogh, Vittorio

    2016-08-01

    Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women. PMID:27393623

  18. Short-form Ron is a novel determinant of ovarian cancer initiation and progression

    PubMed Central

    Moxley, Katherine M.; Wang, Luyao; Welm, Alana L.; Bieniasz, Magdalena

    2016-01-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  19. Emerging and Evolving Ovarian Cancer Animal Models

    PubMed Central

    Bobbs, Alexander S; Cole, Jennifer M; Cowden Dahl, Karen D

    2015-01-01

    Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients. Additionally, multiple genetically engineered mouse models have increased our understanding of possible tissues of origin for OC and what role individual mutations play in establishing ovarian tumors. Many of these models are used to test novel therapeutics. As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options. The goal of this review is to provide an overview of the utility of different mouse models in the study of OC and their suitability for cancer research. PMID:26380555

  20. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

    PubMed Central

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-01-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  1. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression.

    PubMed

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-08-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  2. Safety of Ovarian Tissue Autotransplantation for Cancer Patients

    PubMed Central

    Bockstaele, Laurence; Tsepelidis, Sophie; Dechene, Julie; Englert, Yvon; Demeestere, Isabelle

    2012-01-01

    Cancer treatments can induce premature ovarian failure in almost half of young women suffering from invasive neoplasia. Cryopreservation of ovarian cortex and subsequent autotransplantation of frozen-thawed tissue have emerged as promising alternatives to conventional fertility preservation technologies. However, human ovarian tissue is generally harvested before the administration of gonadotoxic treatment and could be contaminated with malignant cells. The safety of autotransplantation of ovarian cortex remains a major concern for fertility preservation units worldwide. This paper discusses the main tools for detecting disseminated cancer cells currently available, their limitations, and clinical relevance. PMID:22253631

  3. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  4. Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance

    PubMed Central

    Giri, Karuna; Lanza, Ian R.; Nair, K. Sreekumar; Jennings, Nicholas B.; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Basal, Eati; Weaver, Amy L.; Visscher, Daniel W.; Cliby, William; Sood, Anil K.; Bhattacharya, Resham; Mukherjee, Priyabrata

    2013-01-01

    Background Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer. Methods/Principal Findings Using patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics. Conclusion The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer. PMID:24236104

  5. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    PubMed Central

    Pearce, C L; Near, A M; Van Den Berg, D J; Ramus, S J; Gentry-Maharaj, A; Menon, U; Gayther, S A; Anderson, A R; Edlund, C K; Wu, A H; Chen, X; Beesley, J; Webb, P M; Holt, S K; Chen, C; Doherty, J A; Rossing, M A; Whittemore, A S; McGuire, V; DiCioccio, R A; Goodman, M T; Lurie, G; Carney, M E; Wilkens, L R; Ness, R B; Moysich, K B; Edwards, R; Jennison, E; Kjaer, S K; Hogdall, E; Hogdall, C K; Goode, E L; Sellers, T A; Vierkant, R A; Cunningham, J C; Schildkraut, J M; Berchuck, A; Moorman, P G; Iversen, E S; Cramer, D W; Terry, K L; Vitonis, A F; Titus-Ernstoff, L; Song, H; Pharoah, P D P; Spurdle, A B; Anton-Culver, H; Ziogas, A; Brewster, W; Galitovskiy, V; Chenevix-Trench, G

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P⩽0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: ORhomozygous(hom)=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20–6.56, P=0.017, phet across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted. PMID:19127255

  6. MiR-214 suppressed ovarian cancer and negatively regulated semaphorin 4D.

    PubMed

    Liu, Yang; Zhou, Honglin; Ma, Lan; Hou, Youfang; Pan, Jing; Sun, Chunyi; Yang, Yingying; Zhang, Jie

    2016-06-01

    Ovarian cancer is one of the most common human malignancies in women. MiR-214 and semaphorin 4D (sema 4D) were found to be abhorrently expressed and involved in the progress of several kinds of malignant cancers. This study is aimed to investigate the cellular role of miR-214 and demonstrate that miR-214 negatively regulated sema 4D in ovarian cancer cells. The data showed that miR-214 expression was consistently lower in ovarian cancer tissues and cells than those in the normal controls. Over-expression of miR-214 in ovarian cancer SKOV-3 cells inhibited cell proliferation and induced apoptosis. It was suggested that miR-214 functioned as the tumor suppressor in ovarian cancer. Bioinformatic analysis indicated that miR-214 possibly regulated sema 4D by binding the sema 4D messenger RNA (mRNA) 3'-untranslated region (UTR). Sema 4D mRNA and protein levels were up-regulated in ovarian cancer tissues and SKOV-3 cells. Up-regulation of miR-214 in SKOV-3 cell line suppressed the sema 4D expression in both protein and nucleic acid levels. While, down-regulation of miR-214 in SKOV-3 cells would increase sema 4D protein and nucleic acid expression levels. The effects of miR-214 up- and down-regulation on luciferase activities of wild-type (WT) sema 4D 3'-UTR were completely removed upon introduction of mutation in 3'-UTR of WT sema 4D. Therefore, the data also demonstrated that sema 4D was the direct target of miR-214 and was negatively regulated by miR-214 in ovarian cancer cells. PMID:26718213

  7. Why have ovarian cancer mortality rates declined? Part I. Incidence.

    PubMed

    Sopik, Victoria; Iqbal, Javaid; Rosen, Barry; Narod, Steven A

    2015-09-01

    The age-adjusted mortality rate from ovarian cancer in the United States has declined over the past several decades. The decline in mortality might be the consequence of a reduced number of cases (incidence) or a reduction in the proportion of patients who die from their cancer (case-fatality). In part I of this three-part series, we examine rates of ovarian cancer incidence and mortality from the Surveillance Epidemiology and End Results (SEER) registry database and we explore to what extent the observed decline in mortality can be explained by a downward shift in the stage distribution of ovarian cancer (i.e. due to early detection) or by fewer cases of ovarian cancer (i.e. due to a change in risk factors). The proportion of localized ovarian cancers did not increase, suggesting that a stage-shift did not contribute to the decline in mortality. The observed decline in mortality paralleled a decline in incidence. The trends in ovarian cancer incidence coincided with temporal changes in the exposure of women from different birth cohorts to various reproductive risk factors, in particular, to changes in the use of the oral contraceptive pill and to declining parity. Based on recent changes in risk factor propensity, we predict that the trend of the declining age-adjusted incidence rate of ovarian cancer in the United States will reverse and rates will increase in coming years. PMID:26080287

  8. Mesenchymal gene program–expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance

    PubMed Central

    Davidowitz, Rachel A.; Selfors, Laura M.; Iwanicki, Marcin P.; Elias, Kevin M.; Karst, Alison; Piao, Huiying; Ince, Tan A.; Drage, Michael G.; Dering, Judy; Konecny, Gottfried E.; Matulonis, Ursula; Mills, Gordon B.; Slamon, Dennis J.; Drapkin, Ronny; Brugge, Joan S.

    2014-01-01

    Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and protein expression profiles of clearance-competent and clearance-incompetent cells revealed that mesenchymal genes are enriched in tumor populations that display strong clearance activity, while epithelial genes are enriched in those with weak or undetectable activity. Overexpression of transcription factors SNAI1, TWIST1, and ZEB1, which regulate the epithelial-to-mesenchymal transition (EMT), promoted mesothelial clearance in cell lines with weak activity, while knockdown of the EMT-regulatory transcription factors TWIST1 and ZEB1 attenuated mesothelial clearance in ovarian cancer cell lines with strong activity. These findings provide important insights into the mechanisms associated with metastatic progression of ovarian cancer and suggest that inhibiting pathways that drive mesenchymal programs may suppress tumor cell invasion of peritoneal tissues. PMID:24762435

  9. Carboplatin and Paclitaxel or Oxaliplatin and Capecitabine With or Without Bevacizumab as First-Line Therapy in Treating Patients With Newly Diagnosed Stage II-IV or Recurrent Stage I Epithelial Ovarian or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-06-29

    Borderline Ovarian Mucinous Tumor; Ovarian Mucinous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer

  10. Intraoperative radiation therapy in recurrent ovarian cancer

    SciTech Connect

    Yap, O.W. Stephanie . E-mail: stbeast@stanford.edu; Kapp, Daniel S.; Teng, Nelson N.H.; Husain, Amreen

    2005-11-15

    Purpose: To evaluate disease outcomes and complications in patients with recurrent ovarian cancer treated with cytoreductive surgery and intraoperative radiation therapy (IORT). Methods and Materials: A retrospective study of 24 consecutive patients with ovarian carcinoma who underwent secondary cytoreduction and intraoperative radiation therapy at our institution between 1994 and 2002 was conducted. After optimal cytoreductive surgery, IORT was delivered with orthovoltage X-rays (200 kVp) using individually sized and beveled cone applications. Outcomes measures were local control of disease, progression-free interval, overall survival, and treatment-related complications. Results: Of these 24 patients, 22 were available for follow-up analysis. Additional treatment at the time of and after IORT included whole abdominopelvic radiation, 9; pelvic or locoregional radiation, 5; chemotherapy, 6; and no adjuvant treatment, 2. IORT doses ranged from 9-14 Gy (median, 12 Gy). The anatomic sites treated were pelvis (sidewalls, vaginal cuff, presacral area, anterior pubis), para-aortic and paracaval lymph node beds, inguinal region, or porta hepatitis. At a median follow-up of 24 months, 5 patients remain free of disease, whereas 17 patients have recurred, of whom 4 are alive with disease and 13 died from disease. Five patients recurred within the radiation fields for a locoregional relapse rate of 32% and 12 patients recurred at distant sites with a median time to recurrence of 13.7 months. Five-year overall survival was 22% with a median survival of 26 months from time of IORT. Nine patients (41%) experienced Grade 3 toxicities from their treatments. Conclusion: In carefully selected patients with locally recurrent ovarian cancer, combined IORT and tumor reductive surgery is reasonably tolerated and may contribute to achieving local control and disease palliation.

  11. Carboplatin and Paclitaxel With or Without Bevacizumab Compared to Docetaxel, Carboplatin, and Paclitaxel in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Carcinoma (Cancer)

    ClinicalTrials.gov

    2013-03-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Carcinosarcoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  12. An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors.

    PubMed

    Carvalho, S; Lindzen, M; Lauriola, M; Shirazi, N; Sinha, S; Abdul-Hai, A; Levanon, K; Korach, J; Barshack, I; Cohen, Y; Onn, A; Mills, G; Yarden, Y

    2016-01-28

    Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy. PMID:25915843

  13. Value of Symptom-Triggered Diagnostic Evaluation for Ovarian Cancer

    PubMed Central

    Andersen, M. Robyn; Lowe, Kimberly A.; Goff, Barbara A.

    2014-01-01

    Objective To evaluate the potential harms and ovarian cancer outcomes associated with symptom-triggered diagnostic evaluation of all women with symptoms of ovarian cancer. Methods Five thousand-twelve women over age 40 were prospectively enrolled in a cohort study of proactive symptom-triggered diagnostic evaluation. Women who tested positive on a Symptom Index were offered testing with CA125 and transvaginal ultrasound. Results of these tests and any subsequent procedures were recorded. Assessment of ovarian cancer outcomes for all participants through Surveillance, Epidemiology, and End Results (SEER) was performed a year after enrollment was complete. Results A positive Symptom Index was found in 241 (4.8%) of participating patients and 211 (88%) participated in CA125, transvaginal ultrasound, or both CA125 and transvaginal ultrasound. Twenty surgical procedures (laparoscopy, laparotomy, vaginal) were performed in the study population (0.4% of participating women). However, only six (0.12%) were performed for a suspicious ovarian mass and only 4 (0.08%) were performed solely due to study participation. A total of eight ovarian cancers were diagnosed, 31–843days after symptom assessment (50% distant, 50% local or regional). Of the two cancers diagnosed within 6 months, one was Symptom Index-positive. Conclusions Proactive symptom-triggered diagnostic evaluation for ovarian cancer results in minimal unindicated surgery. A small number of ovarian cancers were identified solely on the basis of symptom-triggered diagnostic testing. PMID:24463666

  14. Other Gynecologic Cancers: endometrial, ovarian, vulvar and vaginal cancers.

    PubMed

    Duarte-Franco, Eliane; Franco, Eduardo L

    2004-08-25

    HEALTH ISSUE: In Canada, cancers of the endometrium, ovaries, vulva, vagina, placenta and adnexa account for 11% of all malignant neoplasms in women and 81% of all genital cancers. Although the incidence and mortality from vulvar and vaginal cancers are very low, endometrium and ovarian cancer are important public health problems. KEY FINDINGS: In Canada, there has been no appreciable improvement in survival for women with advanced endometrial (EC) or ovarian cancer (OC) over the past 30 years. The prognosis of EC is good for most patients because diagnosis is made at early stages. However, survival of OC is poor; more than 70% of cases are diagnosed at late stages. Up to 10% of OCs is linked to familial aggregation. Cancers of the vulva and of the vagina are very rare. The survival experience for women with the latter is worse than for those with the former. Both share many risk factors with cervical cancer and the recent developments in the study of HPV infection should be applicable to these diseases as well. Of particular interest will be the advent of vaccines for the primary prevention of HPV infection. DATA GAPS AND RECOMMENDATIONS: At present, the best available means to diagnose gynecologic malignancies is a detailed clinical examination, considering the totality of information on potential and proven risk factors, such as age, reproductive health, sexual practices, use unopposed estrogens or of oral contraceptives or tubal ligation, obesity, diet, smoking, and the familial clustering of some of these cancers. PMID:15345077

  15. Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer

    PubMed Central

    Sölétormos, György; Duffy, Michael J.; Othman Abu Hassan, Suher; Verheijen, René H.M.; Tholander, Bengt; Bast, Robert C.; Gaarenstroom, Katja N.; Sturgeon, Catharine M.; Bonfrer, Johannes M.; Petersen, Per Hyltoft; Troonen, Hugo; CarloTorre, Gian; Kanty Kulpa, Jan; Tuxen, Malgorzata K.; Molina, Raphael

    2016-01-01

    Objective To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. Methods Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. Results Because of its low sensitivity (50–62% for early stage epithelial ovarian cancer) and limited specificity (94–98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. Conclusions At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin. PMID:26588231

  16. Data Mining for Identification of Molecular Targets in Ovarian Cancer.

    PubMed

    Villegas-Ruiz, Vanessa; Juarez-Mendez, Sergio

    2016-01-01

    Ovarian cancer is possibly the sixth most common malignancy worldwide, in Mexico representing the fourth leading cause of gynecological cancer death more than 70% being diagnosed at an advanced stage and the survival being very poor. Ovarian tumors are classified according to histological characteristics, epithelial ovarian cancer as the most common (~80%). We here used high-density microarrays and a systems biology approach to identify tissue-associated deregulated genes. Non-malignant ovarian tumors showed a gene expression profile associated with immune mediated inflammatory responses (28 genes), whereas malignant tumors had a gene expression profile related to cell cycle regulation (1,329 genes) and ovarian cell lines to cell cycling and metabolism (1,664 genes). PMID:27221839

  17. Angiogenesis inhibitors for the treatment of ovarian cancer

    PubMed Central

    Gaitskell, Kezia; Martinek, Igor; Bryant, Andrew; Kehoe, Sean; Nicum, Shibani; Morrison, Jo

    2014-01-01

    Background Many women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be. Objectives To compare the effectiveness and toxicities of angiogenesis inhibitors in the treatment of ovarian cancer. Search methods We sought to identify completed randomised controlled trials (RCTs) by searching The Cochrane Gynaecological Cancer Review Group’s Trial Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE and EMBASE (1990 to October 2010). We also searched registers of clinical trials, and contacted investigators of completed and ongoing trials for further information. Selection criteria Randomised controlled studies comparing angiogenesis inhibitors with either standard chemotherapy or no treatment, in women with ovarian cancer. Data collection and analysis Two independent authors carried out data collection and extraction. We used a random-effects model for pooling data. Main results We did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants. Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced

  18. Prognostic values of aldehyde dehydrogenase 1 isoenzymes in ovarian cancer

    PubMed Central

    Ma, Yu-mei; Zhao, Shan

    2016-01-01

    Aldehyde dehydrogenase 1 (ALDH1) activity has been used as a functional stem cell marker to isolate cancer stem cells in different cancer types, including ovarian cancer. However, which ALDH1’s isoenzymes are contributing to ALDH1 activity in ovarian cancer remains elusive. In addition, the prognostic value of an individual ALDH1 isoenzyme in ovarian cancer is not clear. Thus, we accessed the prognostic value of ALDH1 isoenzymes in ovarian cancer patients through the “Kaplan–Meier plotter” online database, which can be used to determine the effect of the genes on ovarian cancer prognosis. We found that high mRNA expression of five ALDH1 isoenzymes, such as ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, and ALDH1L1, was not correlated with overall survival (OS) for all 1,306 ovarian cancer patients. In addition, all five of the ALDH1 isoenzymes’ high mRNA expression was found to be uncorrelated with OS in serous cancer or endometrioid cancer patients. However, ALDH1A3’s high mRNA expression is associated with worse OS in grade II ovarian cancer patients, hazard ratio (HR) 1.53 (1.14–2.07), P=0.005. ALDH1A2’s high mRNA expression is significantly associated with worse OS in TP53 wild-type ovarian cancer patients, HR 2.86 (1.56–5.08), P=0.00036. In addition, ALDH1A3’s high mRNA expression is significantly associated with better OS in TP53 wild-type ovarian cancer patients, HR 0.56 (0.32–1.00), P=0.04. Our results indicate that although ALDH1 isoenzyme mRNA might not be a prognostic marker for overall ovarian cancer patients, some isoenzymes, such as ALDH1A2 and ALDH1A3, might be a good prognostic marker for some types of ovarian cancer patients. PMID:27110126

  19. Carboplatin, Paclitaxel, Bevacizumab, and Veliparib in Treating Patients With Newly Diagnosed Stage II-IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-08-03

    Fallopian Tube Carcinosarcoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Neoplasm; Fallopian Tube Transitional Cell Carcinoma; Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Tumor; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  20. Role of minimally invasive surgery in ovarian cancer.

    PubMed

    Nezhat, Farr R; Pejovic, Tanja; Finger, Tamara N; Khalil, Susan S

    2013-01-01

    The standard treatment of ovarian cancer includes upfront surgery with intent to accurately diagnose and stage the disease and to perform maximal cytoreduction, followed by chemotherapy in most cases. Surgical staging of ovarian cancer traditionally has included exploratory laparotomy with peritoneal washings, hysterectomy, salpingo-oophorectomy, omentectomy, multiple peritoneal biopsies, and possible pelvic and para-aortic lymphadenectomy. In the early 1990s, pioneers in laparoscopic surgery used minimally invasive techniques to treat gynecologic cancers, including laparoscopic staging of early ovarian cancer and primary and secondary cytoreduction in advanced and recurrent disease in selected cases. Since then, the role of minimally invasive surgery in gynecologic oncology has been continually expanding, and today advanced laparoscopic and robotic-assisted laparoscopic techniques are used to evaluate and treat cervical and endometrial cancer. However, the important question about the place of the minimally invasive approach in surgical treatment of ovarian cancer remains to be evaluated and answered. Overall, the potential role of minimally invasive surgery in treatment of ovarian cancer is as follows: i) laparoscopic evaluation, diagnosis, and staging of apparent early ovarian cancer; ii) laparoscopic assessment of feasibility of upfront surgical cytoreduction to no visible disease; iii) laparoscopic debulking of advanced ovarian cancer; iv) laparoscopic reassessment in patients with complete remission after primary treatment; and v) laparoscopic assessment and cytoreduction of recurrent disease. The accurate diagnosis of suspect adnexal masses, the safety and feasibility of this surgical approach in early ovarian cancer, the promise of laparoscopy as the most accurate tool for triaging patients with advanced disease for surgery vs upfront chemotherapy or neoadjuvant chemotherapy, and its potential in treatment of advanced cancer have been documented and

  1. Modulation of redox signaling promotes apoptosis in epithelial ovarian cancer cells

    PubMed Central

    Jiang, Zhongliang; Fletcher, Nicole M.; Ali-Fehmi, Rouba; Diamond, Michael P.; Abu-Soud, Husam M.; Munkarah, Adnan R.; Saed, Ghassan M.

    2014-01-01

    Objective Epithelial ovarian cancer (EOC) cells are known to be resistant to apoptosis through a mechanism that may involve alteration in their redox balance. NADPH oxidase is a major source of intracellular superoxide, which is converted to the less toxic product by superoxide dismutase (SOD). Superoxide contributes to hypoxia inducible factor (HIF)-1α stabilization. We sought to determine the effects of inhibiting the generation of intracellular reactive oxygen species (ROS) on apoptosis of EOC cells. Methods Diphenyleneiodonium (DPI), an irreversible ROS inhibitor, was used to inhibit the generation of ROS in EOC cell lines, SKOV-3 and MDAH-2774, followed by assessment of apoptosis, NADPH oxidase, SOD3 and HIF-1α expression. A combination of immunohistochemistry, immunoprecipitation/western blot, and real-time RT-PCR were utilized to evaluate the expression of these enzymes in EOC cells as well as normal ovarian tissue and ovarian cancer tissue specimens. Results DPI treatment significantly induced apoptosis in both EOC cell lines as evident by increased caspase-3 activity and TUNEL assay. Additionally, both EOC cell lines were found to express NADPH oxidase, HIF-1α, and SOD3, which were highly sensitive to DPI treatment. DPI treatment resulted in reduced NADPH oxidase, SOD3 and HIF-1α levels. Furthermore, ovarian cancer tissues were found to manifest higher NADPH oxidase levels as compared to normal ovarian tissues. Conclusions These data suggest that lowering oxidative stress, possibly through the inhibition of NADPH oxidase, induces apoptosis in ovarian cancer cells and may serve as a potential target for cancer therapy. PMID:21620448

  2. Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress

    PubMed Central

    Wang, Qian; Xue, Liang; Zhang, Xiaoyu; Bu, Shixia; Zhu, Xueliang; Lai, Dongmei

    2016-01-01

    ABSTRACT RNA-Seq and gene set enrichment anylysis revealed that ovarian cancer associated fibroblasts (CAFs) are mitotically active compared with normal fibroblasts (NFs). Cellular senescence is observed in CAFs treated with H2O2 as shown by elevated SA-β-gal activity and p21 (WAF1/Cip1) protein levels. Reactive oxygen species (ROS) production and p21 (WAF1/Cip1) elevation may account for H2O2-induced CAFs cell cycle arrest in S phase. Blockage of autophagy can increase ROS production in CAFs, leading to cell cycle arrest in S phase, cell proliferation inhibition and enhanced sensitivity to H2O2-induced cell death. ROS scavenger NAC can reduce ROS production and thus restore cell viability. Lactate dehydrogenase A (LDHA), monocarboxylic acid transporter 4 (MCT4) and superoxide dismutase 2 (SOD2) were up-regulated in CAFs compared with NFs. There was relatively high lactate content in CAFs than in NFs. Blockage of autophagy decreased LDHA, MCT4 and SOD2 protein levels in CAFs that might enhance ROS production. Blockage of autophagy can sensitize CAFs to chemotherapeutic drug cisplatin, implicating that autophagy might possess clinical utility as an attractive target for ovarian cancer treatment in the future. PMID:27074587

  3. Vaccinia Virus Induces Programmed Necrosis in Ovarian Cancer Cells

    PubMed Central

    Whilding, Lynsey M; Archibald, Kyra M; Kulbe, Hagen; Balkwill, Frances R; Öberg, Daniel; McNeish, Iain A

    2013-01-01

    The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-α, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events. PMID:23985697

  4. Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress.

    PubMed

    Wang, Qian; Xue, Liang; Zhang, Xiaoyu; Bu, Shixia; Zhu, Xueliang; Lai, Dongmei

    2016-05-18

    RNA-Seq and gene set enrichment anylysis revealed that ovarian cancer associated fibroblasts (CAFs) are mitotically active compared with normal fibroblasts (NFs). Cellular senescence is observed in CAFs treated with H2O2 as shown by elevated SA-β-gal activity and p21 (WAF1/Cip1) protein levels. Reactive oxygen species (ROS) production and p21 (WAF1/Cip1) elevation may account for H2O2-induced CAFs cell cycle arrest in S phase. Blockage of autophagy can increase ROS production in CAFs, leading to cell cycle arrest in S phase, cell proliferation inhibition and enhanced sensitivity to H2O2-induced cell death. ROS scavenger NAC can reduce ROS production and thus restore cell viability. Lactate dehydrogenase A (LDHA), monocarboxylic acid transporter 4 (MCT4) and superoxide dismutase 2 (SOD2) were up-regulated in CAFs compared with NFs. There was relatively high lactate content in CAFs than in NFs. Blockage of autophagy decreased LDHA, MCT4 and SOD2 protein levels in CAFs that might enhance ROS production. Blockage of autophagy can sensitize CAFs to chemotherapeutic drug cisplatin, implicating that autophagy might possess clinical utility as an attractive target for ovarian cancer treatment in the future. PMID:27074587

  5. BRCA1 as a nicotinamide adenine dinucleotide (NAD)-dependent metabolic switch in ovarian cancer

    PubMed Central

    Li, Da; Chen, Na-Na; Cao, Ji-Min; Sun, Wu-Ping; Zhou, Yi-Ming; Li, Chun-Yan; Wang, Xiu-Xia

    2014-01-01

    Both hereditary factors (e.g., BRCA1) and nicotinamide adenine dinucleotide (NAD)-dependent metabolic pathways are implicated in the initiation and progression of ovarian cancer. However, whether crosstalk exists between BRCA1 and NAD metabolism remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation and promoter methylation) were accompanied by elevated levels of NAD; (ii) the knockdown or overexpression of BRCA1 was an effective way to induce an increase or decrease of nicotinamide phosphoribosyltransferase (Nampt)-related NAD synthesis, respectively; and (iii) BRCA1 expression patterns were inversely correlated with NAD levels in human ovarian cancer specimens. In addition, it is worth noting that: (i) NAD incubation induced increased levels of BRCA1 in a concentration-dependent manner; (ii) Nampt knockdown-mediated reduction in NAD levels was effective at inhibiting BRCA1 expression; and (iii) the overexpression of Nampt led to higher NAD levels and a subsequent increase in BRCA1 levels in primary ovarian cancer cells and A2780, HO-8910 and ES2 ovarian cancer cell lines. These results highlight a novel link between BRCA1 and NAD. Our findings imply that genetic (e.g., BRCA1 inactivation) and NAD-dependent metabolic pathways are jointly involved in the malignant progression of ovarian cancer. PMID:25486197

  6. Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells

    PubMed Central

    Ma, Liwei; Wang, Hongjun; Wang, Chunyan; Su, Jing; Xie, Qi; Xu, Lu; Yu, Yang; Liu, Shibing; Li, Songyan; Xu, Ye; Li, Zhixin

    2016-01-01

    Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca2+ concentration, including cytosolic and mitochondrial Ca2+ in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca2+ overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance. PMID:27330840

  7. Quantitative analysis of cell-free DNA in ovarian cancer

    PubMed Central

    SHAO, XUEFENG; He, YAN; JI, MIN; CHEN, XIAOFANG; QI, JING; SHI, WEI; HAO, TIANBO; JU, SHAOQING

    2015-01-01

    The aim of the present study was to investigate the association between cell-free DNA (cf-DNA) levels and clinicopathological characteristics of patients with ovarian cancer using a branched DNA (bDNA) technique, and to determine the value of quantitative cf-DNA detection in assisting with the diagnosis of ovarian cancer. Serum specimens were collected from 36 patients with ovarian cancer on days 1, 3 and 7 following surgery, and additional serum samples were also collected from 22 benign ovarian tumor cases, and 19 healthy, non-cancerous ovaries. bDNA techniques were used to detect serum cf-DNA concentrations. All data were analyzed using SPSS version 18.0. The cf-DNA levels were significantly increased in the ovarian cancer group compared with those of the benign ovarian tumor group and healthy ovarian group (P<0.01). Furthermore, cf-DNA levels were significantly increased in stage III and IV ovarian cancer compared with those of stages I and II (P<0.01). In addition, cf-DNA levels were significantly increased on the first day post-surgery (P<0.01), and subsequently demonstrated a gradual decrease. In the ovarian cancer group, the area under the receiver operating characteristic curve of cf-DNA and the sensitivity were 0.917 and 88.9%, respectively, which was higher than those of cancer antigen 125 (0.724, 75%) and human epididymis protein 4 (0.743, 80.6%). There was a correlation between the levels of serum cf-DNA and the occurrence and development of ovarian cancer in the patients evaluated. bDNA techniques possessed higher sensitivity and specificity than other methods for the detection of serum cf-DNA in patients exhibiting ovarian cancer, and bDNA techniques are more useful for detecting cf-DNA than other factors. Thus, the present study demonstrated the potential value for the use of bDNA as an adjuvant diagnostic method for ovarian cancer. PMID:26788153

  8. Antigen-specific immunotherapy of cervical and ovarian cancer

    PubMed Central

    Hung, Chien-fu; Wu, TC; Monie, Archana; Roden, Richard

    2009-01-01

    Summary We contrast the efforts to treat ovarian cancer and cervical cancer through vaccination because of their different pathobiology. A plethora of approaches have been developed for therapeutic vaccination against cancer, many of which target defined tumor-associated antigens (TAAs). Persistent infection with oncogenic human papillomavirus (HPV) types is necessary cause of cervical cancer. Furthermore, cervical cancer patients frequently mount both humoral and T cell immune responses to the HPV E6 and E7 oncoproteins, whose expression is required for the transformed phenotype. Numerous vaccine studies target these viral TAAs, including recent trials that may enhance clearance of pre-malignant disease. By contrast little is known about the etiology of epithelial ovarian cancer. Although it is clear that p53 mutation or loss is a critical early event in the development of epithelial ovarian cancer, no precursor lesion has been described for the most common serous histotype, and even the location of its origin is debated. These issues have complicated the selection of appropriate ovarian TAAs and the design of vaccines. Here we focus on mesothelin as a promising ovarian TAA because it is overexpressed and immunogenic at high frequency in patients, is displayed on the cell surface and potentially contributes to ovarian cancer biology. PMID:18363994

  9. Doxycycline Inducible Kruppel-Like Factor 4 Lentiviral Vector Mediates Mesenchymal to Epithelial Transition in Ovarian Cancer Cells

    PubMed Central

    Chen, Zixuan; Wang, Yinan; Liu, Wen; Zhao, Guannan; Lee, Suechin; Balogh, Andrea; Zou, Yanan; Guo, Yuqi; Zhang, Zhan; Gu, Weiwang; Li, Chengyao; Tigyi, Gabor; Yue, Junming

    2014-01-01

    Ovarian cancer presents therapeutic challenges due to its typically late detection, aggressive metastasis, and therapeutic resistance. The transcription factor Krüppel-like factor 4 (KLF4) has been implicated in human cancers as a tumor suppressor or oncogene, although its role depends greatly on the cellular context. The role of KLF4 in ovarian cancer has not been elucidated in mechanistic detail. In this study, we investigated the role of KLF4 in ovarian cancer cells by transducing the ovarian cancer cell lines SKOV3 and OVCAR3 with a doxycycline-inducible KLF4 lentiviral vector. Overexpression of KLF4 reduced cell proliferation, migration, and invasion. The epithelial cell marker gene E-cadherin was significantly upregulated, whereas the mesenchymal cell marker genes vimentin, twist1and snail2 (slug) were downregulated in both KLF4-expressing SKOV3 and OVCAR3 cells. KLF4 inhibited the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition (EMT) in ovarian cancer cells. Taken together, our data demonstrate that KLF4 functions as a tumor suppressor gene in ovarian cancer cells by inhibiting TGFβ-induced EMT. PMID:25137052

  10. Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

    PubMed Central

    Chan, David W.; Hui, Winnie W. Y.; Cai, Patty C. H.; Liu, Michelle X.; Yung, Mingo M. H.; Mak, Celia S. L.; Leung, Thomas H. Y.; Chan, Karen K. L.; Ngan, Hextan Y. S.

    2012-01-01

    Ovarian cancer is a highly lethal disease with poor prognosis and especially in high-grade tumor. Emerging evidence has reported that aberrant upregulation and activation of GRB7, ERK as well as FOXM1 are closely associated with aggresivenesss of human cancers. However, the interplay between these factors in the pathogenesis of human cancers still remains unclear. In this study, we found that GRB7 (P<0.0001), ERK phosphorylation (P<0.0001) and FOXM1 (P = 0.001) were frequently increased and associated with high-grade tumors, as well as a high tendency in association with advanced stage ovarian cancer by immunohistochemical analysis. Intriguingly, the expressions of GRB7 (P<0.0001), ERK phosphorylation (P<0.001) and FOXM1 (P<0.001) showed a significant stepwise increase pattern along Grade 1 to Grade 3 ovarian cancers. Biochemical studies using western blot analysis demonstrated that enforced expression or knockdown of GRB7 showed GRB7 could elevate the levels of ERK phosphorylation and FOXM1, whereas enforced expression of FOXM1 could not alter levels of GRB7 and ERK phosphorylation. But inhibition of ERK signaling by U0126 or PD98059 could reduce the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, suggesting that GRB7, ERK and FOXM1 are regulated orderly. Moreover, inhibition of ERK activity by U0126 or PD98059, or decreased FOXM1 expression by Thiostrepton significantly inhibited cell migration/invasion, tumor growth in vitro and in vivo. Collectively, our findings confer that targeting GRB7/ERK/FOXM1 signaling cascade may be a promising molecular therapeutic choice in combating ovarian cancer. PMID:23285101

  11. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    SciTech Connect

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

    2014-02-07

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

  12. Granisetron, Aprepitant, and Dexamethasone in Preventing Nausea and Vomiting in Patients Receiving Chemotherapy for Stage II, III, or IV Ovarian Cancer

    ClinicalTrials.gov

    2016-03-16

    Malignant Ovarian Mixed Epithelial Tumor; Nausea and Vomiting; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  13. Nectin 4 Overexpression in Ovarian Cancer Tissues and Serum

    PubMed Central

    DeRycke, Melissa S.; Pambuccian, Stefan E.; Gilks, C. Blake; Kalloger, Steve E.; Ghidouche, Abderrezak; Lopez, Marc; Bliss, Robin L.; Geller, Melissa A.; Argenta, Peter A.; Harrington, Katherine M.; Skubitz, Amy P.N.

    2011-01-01

    Early detection of ovarian cancer is difficult owing to the lack of specific and sensitive tests available. Previously, we found expression of nectin 4 to be increased in ovarian cancer compared with normal ovaries. Reverse transcriptase–polymerase chain reaction (RT-PCR) and quantitative RT-PCR validated the overexpression of nectin 4 messenger RNA in ovarian cancer compared with normal ovarian cell lines and tissues. Protein levels of nectin 4 were elevated in ovarian cancer cell lines and tissue compared with normal ovarian cell lines as demonstrated by Western immunoblotting, flow cytometry, and immunohistochemical staining of tissue microarray slides. Cleaved nectin 4 was detectable in a number of patient serum samples by enzyme-linked immunosorbent assay. In patients with benign gynecologic diseases with high serum CA125 levels, nectin 4 was not detected in the majority of cases, suggesting that nectin 4 may serve as a potential biomarker that helps discriminate benign gynecologic diseases from ovarian cancer in a panel with CA125. PMID:20959669

  14. Surgery and Chemotherapy With or Without Chemotherapy After Surgery in Treating Patients With Ovarian, Fallopian Tube, Uterine, or Peritoneal Cancer

    ClinicalTrials.gov

    2016-08-18

    Recurrent Uterine Corpus Cancer; Recurrent Fallopian Tube Cancer; Recurrent Ovarian Cancer; Recurrent Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cavity Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cavity Cancer; Stage IIIC Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cavity Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cavity Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  15. Docosahexaenoic Acid Modulates Invasion and Metastasis of Human Ovarian Cancer via Multiple Molecular Pathways

    PubMed Central

    Wang, Ying-Chun; Wu, Yi-Nan; Wang, Su-Li; Lin, Qing-Hua; He, Ming-Fang; Liu, Qiao-lin; Wang, Jin-Hua

    2016-01-01

    Objective We investigated the effect of docosahexaenoic acid (DHA) on the invasion and metastasis of ovarian cancer cells (A2780, HO8910, and SKOV-3). Methods Cytotoxicity assay was performed to determine the optimal doses of DHA in this experiment. The effects of DHA on invasion ability were assessed by invasion assay. The expressions of messenger RNA and/or proteins associated with invasion or metastasis were detected by quantitative Real Time-Polymerase Chain Reaction or Western blot. The effect of DHA on cell metastasis was assessed in xenograft model of zebrafish. Results Docosahexaenoic acid and α-linolenic acid could reduce the cell vitalities in dose-dependent manner. However, DHA inhibited the invasion and metastasis of ovarian cancer cells, but α-linolenic acid did not (**P < 0.01). Docosahexaenoic acid could downregulate the expressions of WAVE3, vascular endothelial cell growth factor, and MMP-9, and upregulate KISS-1, TIMP-1, and PPAR-γ, which negatively correlated with cell invasion and metastasis (*P < 0.05). Docosahexaenoic acid restrained the development of subintestinal vessels and cancer cell metastasis in xenograft model of zebrafish (**P < 0.01). Conclusions Docosahexaenoic acid inhibited the invasion and metastasis of ovarian cancer cells in vitro and in vivo through the modulation of NF-κB signaling pathway, suggesting that DHA is a promising candidate for ovarian cancer therapy. PMID:27258728

  16. Municipal distribution of ovarian cancer mortality in Spain

    PubMed Central

    Lope, Virginia; Pollán, Marina; Pérez-Gómez, Beatriz; Aragonés, Nuria; Vidal, Enrique; Gómez-Barroso, Diana; Ramis, Rebeca; García-Pérez, Javier; Cabanes, Anna; López-Abente, Gonzalo

    2008-01-01

    Background Spain was the country that registered the greatest increases in ovarian cancer mortality in Europe. This study describes the municipal distribution of ovarian cancer mortality in Spain using spatial models for small-area analysis. Methods Smoothed relative risks of ovarian cancer mortality were obtained, using the Besag, York and Molliè autoregressive spatial model. Standardised mortality ratios, smoothed relative risks, and distribution of the posterior probability of relative risks being greater than 1 were depicted on municipal maps. Results During the study period (1989–1998), 13,869 ovarian cancer deaths were registered in 2,718 Spanish towns, accounting for 4% of all cancer-related deaths among women. The highest relative risks were mainly concentrated in three areas, i.e., the interior of Barcelona and Gerona (north-east Spain), the north of Lugo and Asturias (north-west Spain) and along the Seville-Huelva boundary (in the south-west). Eivissa (Balearic Islands) and El Hierro (Canary Islands) also registered increased risks. Conclusion Well established ovarian cancer risk factors might not contribute significantly to the municipal distribution of ovarian cancer mortality. Environmental and occupational exposures possibly linked to this pattern and prevalent in specific regions, are discussed in this paper. Small-area geographical studies are effective instruments for detecting risk areas that may otherwise remain concealed on a more reduced scale. PMID:18789142

  17. Defining Therapy for Recurrent Platinum-sensitive Ovarian Cancer

    Cancer.gov

    In this phase III clinical trial, women with platinum-sensitive, recurrent ovarian epithelial, fallopian tube, or primary peritoneal cancer will be randomly assigned to undergo secondary cytoreductive surgery, if they are candidates for such surgery, and

  18. Discovery – BRCA Connection to Breast and Ovarian Cancer

    Cancer.gov

    NCI-funded research helped identify inherited BRCA1 and BRCA2 genetic mutations and their connection to breast and ovarian cancer. From this research, a screening test was also developed to help patients make informed decisions about their health.

  19. What Will Happen After Treatment for Ovarian Cancer?

    MedlinePlus

    ... general physical exam and blood tests for tumor markers that help recognize recurrence. For epithelial ovarian cancer, ... with your doctor. The choice of which tumor marker blood tests to check depends on the type ...

  20. Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients

    Cancer.gov

    Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival.

  1. Fertility drugs, reproductive strategies and ovarian cancer risk.

    PubMed

    Tomao, Federica; Lo Russo, Giuseppe; Spinelli, Gian Paolo; Stati, Valeria; Prete, Alessandra Anna; Prinzi, Natalie; Sinjari, Marsela; Vici, Patrizia; Papa, Anselmo; Chiotti, Maria Stefania; Benedetti Panici, Pierluigi; Tomao, Silverio

    2014-01-01

    Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer. PMID:24829615

  2. [Bone marrow involvement in ovarian cancer determined by immunohistochemical methods].

    PubMed

    Gabriel, M; Obrebowska, A; Spaczyński, M

    2000-01-01

    Atypical epithelial cells in the bone marrow of patients with ovarian cancer were evaluated using immunohistochemical techniques. We investigated cytospin preparations of bone marrow taken from 9 women with benign ovarian tumors and 59 women with malignant ovarian tumors. Two monoclonal antibodies (NCL-C11 and NCL-CA 125) were used. With both antibodies we were able to detect keratin and CA 125 antigen expression in the bone marrow of 9 (18.4%) of the patients with ovarian cancer. With regard to the wide histological differentiation of ovarian carcinomas, the presence of atypical epithelial cells in the bone marrow was required as a prognostic factor for survival and relapses. This should be investigated in a larger study group. PMID:11326158

  3. A Molecularly Targeted Theranostic Probe for Ovarian Cancer

    PubMed Central

    Chen, Wenxue; Bardhan, Rizia; Bartels, Marc; Perez-Torres, Carlos; Pautler, Robia G.; Halas, Naomi J.; Joshi, Amit

    2014-01-01

    Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in ovarian cancer because of its participation in signaling pathway regulating cellular proliferation, differentiation, motility, and survival. Currently, effective diagnostic and therapeutic schemes are lacking for treating ovarian cancer and consequently ovarian cancer has a high mortality rate. While HER2 receptor expression does not usually affect the survival rates of ovarian cancer to the same extent as in breast cancer, it can be employed as a docking site for directed nanotherapies in cases with de novo or acquired chemotherapy resistance. In this study, we have exploited a novel gold nanoshell-based complex (nanocomplex) for targeting, dual modal imaging, and photothermal therapy of HER2 overexpressing and drug resistant ovarian cancer OVCAR3 cells in vitro. The nanocomplexes are engineered to simultaneously provide contrast as fluorescence optical imaging probe and a magnetic resonance imaging (MRI) agent. Both immunofluorescence staining and MRI successfully demonstrate that nanocomplex-anti-HER2 conjugates specifically bind to OVCAR3 cells as opposed to the control, MDA-MB-231 cells, which have low HER2 expression. In addition, nanocomplexes targeted to OVCAR3 cells, when irradiated with near infrared (NIR) laser result in selective destruction of cancer cells through photothermal ablation. We also demonstrate that NIR light therapy and the nanocomplexes by themselves are non-cytotoxic in vitro. To the best of our knowledge, this is the first demonstration of a successful integration of dual modal bioimaging with photothermal cancer therapy for treatment of ovarian cancer. Based on their efficacy in vitro, these nanocomplexes are highly promising for image guided photo-thermal therapy of ovarian cancer as well as other HER2 overexpressing cancers. PMID:20371708

  4. Nuclear medicine for imaging of epithelial ovarian cancer.

    PubMed

    Abedi, Seyed Mohammad; Mardanshahi, Alireza; Shahhosseini, Roza; Hosseinimehr, Seyed Jalal

    2016-05-01

    Cancer is one of the leading causes of mortality worldwide. Usually, the diagnosis of cancer at an early stage is important to facilitate proper treatment and survival. Nuclear medicine has been successfully used in the diagnosis, staging, therapy and monitoring of cancers. Single-photon emission computed tomography and PET-based companion imaging agents are in development for use as a companion diagnostic tool for patients with ovarian cancer. The present review discusses the basic and clinical studies related to the use of radiopharmaceuticals in the diagnosis and management of ovarian cancer, focusing on their utility and comparing them with other imaging techniques such as computed tomography and MRI. PMID:26984362

  5. Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis

    PubMed Central

    Huang, Haizhi; Chen, Allen Y.; Rojanasakul, Yon; Ye, Xingqian; Rankin, Gary O.; Chen, Yi Charlie

    2015-01-01

    Galangin and myricetin are flavonoids isolated from vegetables and fruits which exhibit anti-proliferative activity in human cancer cells. In this study, their anti-angiogenic effects were investigated with in vitro (HUVEC) and in vivo (CAM) models, which showed that galangin and myricetin inhibited angiogenesis induced by OVCAR-3 cells. The molecular mechanisms through which galangin and myricetin suppress angiogenesis were also studied. It was observed that galangin and myricetin inhibited secretion of the key angiogenesis mediator vascular endothelial growth factor (VEGF) and decreased levels of p-Akt, p-70S6K and hypoxia-inducible factor-1α (HIF-1α) proteins in A2780/CP70 and OVCAR-3 cells. Transient transfection experiments showed that galangin and myricetin inhibited secretion of VEGF by the Akt/p70S6K/ HIF-1α pathway. Moreover, a novel pathway, p21/HIF-1α/VEGF, was found to be involved in the inhibitory effect of myricetin on angiogenesis in OVCAR-3 cells. These data suggest that galangin and myricetin might serve as potential anti-angiogenic agents in the prevention of ovarian cancers dependent on new blood vessel networks. PMID:26113875

  6. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    PubMed Central

    2010-01-01

    Background Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. Methods The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. Results We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. Conclusions The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism

  7. A correlation between altered O-GlcNAcylation, migration and with changes in E-cadherin levels in ovarian cancer cells

    SciTech Connect

    Jin, Feng-zhen; Yu, Chao; Zhao, De-zhang; Wu, Ming-jun; Yang, Zhu

    2013-06-10

    O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins. In recent years, the roles of O-GlcNAcylation in several human malignant tumors have been investigated, and O-GlcNAcylation was found to be linked to cellular features relevant to metastasis. In this study, we modeled four diverse ovarian cancer cells and investigated the effects of O-GlcNAcylation on ovarian cancer cell migration. We found that total O-GlcNAcylation level was elevated in HO-8910PM cells compared to OVCAR3 cells. Additionally, through altering the total O-GlcNAcylation level by OGT silencing or OGA inhibition, we found that the migration of OVCAR3 cells was dramatically enhanced by PUGNAc and Thiamet G treatment, and the migration ability of HO-8910PM cells was significantly inhibited by OGT silencing. Furthermore, we also found that the expression of E-cadherin, an O-GlcNAcylated protein in ovarian cancer cells, was reduced by OGA inhibition in OVCAR3 cells and elevated by OGT silencing in HO-8910PM cells. These results indicate that O-GlcNAcylation could enhance ovarian cancer cell migration and decrease the expression of E-cadherin. Our studies also suggest that O-GlcNAcylation might become another potential target for the therapy of ovarian cancer. -- Highlights: • We examine the migration potential of diverse ovarian cancer cells. • We examine the total O-GlcNAcylation level of diverse ovarian cancer cells. • Increasing O-GlcNAcylation level will enhance the migration of ovarian cancer cells. • Reducing O-GlcNAcylation level will inhibit the migration of ovarian cancer cells. • The mechanism explains O-GlcNAcylation enhance ovarian cancer cell migration.

  8. Recently identified drug resistance biomarkers in ovarian cancer.

    PubMed

    Davidson, Ben

    2016-05-01

    Ovarian cancer, consisting mainly of ovarian carcinoma, is the most lethal gynecologic malignancy. Improvements in outcome for patients with advanced-stage disease are limited by intrinsic and acquired chemoresistance and by tumor heterogeneity at different anatomic sites and along disease progression. Molecules and cellular pathways mediating chemoresistance appear to be different for the different histological types of ovarian carcinoma, with most recent research focusing on serous and clear cell carcinoma. This review discusses recent data implicating various biomarkers in chemoresistance in this cancer, with focus on studies in which clinical specimens have been central. PMID:26895188

  9. HOTAIR Interacting with MAPK1 Regulates Ovarian Cancer skov3 Cell Proliferation, Migration, and Invasion

    PubMed Central

    Yiwei, Tang; Hua, Huang; Hui, Guo; Mao, Meng; Xiang, Long

    2015-01-01

    Background The aim of this study was to evaluate the effect of when silencing HOTAIR in ovarian cancer skov3 cells on proliferation, migration, and invasion, and to elucidate the mechanism by which this occurs. Material/Methods We detected the mRNA level of HOTAIR (HOX antisense intergenic RNA) and MAPK1 (mitogen-activated protein kinase 1) in ovarian cancer SKOV3, ES-2, OVCAR3, A2780, and COC1 cell lines. We detected the mRNA level of HOTAIR and MAPK1 in ovarian SKOV3 when transected with miR-1, miR-214-3p, or miR-330-5p. We detected the mRNA and protein level of MAPK1 when silencing HOTAIR. We detected the expression of HOTAIR when silencing MAPK1. Then we detected the proliferation, migration, and invasion in ovarian cancer skov3 after silencing HOTAIR or MAPK1. Results The expression of HOTAIR and MAPK1 in ovarian SKOV3, ES-2, and OVCAR3 increased compared with A2780 and COC1 cells (P<0.05). The mRNA level of HOTAIR and MAPK1 in ovarian SKOV3 decreased when transected with miR-1, miR-214-3p, or miR-330-5p compared to negative control (p<0.05). The mRNA and protein level of MAPK1 was decreased when silencing HOTAIR and the mRNA level of HOTAIR was decreased when silencing MAPK1 (p<0.05). The proliferation, migration, and invasion was inhibited in ovarian SKOV3 after silencing HOTAIR or MAPK1 (p<0.05). Conclusions HOTAIR can promote proliferation, migration, and invasion in ovarian SKOV3 cells as a competing endogenous RNA. PMID:26117268

  10. Proteomics of ovarian cancer: functional insights and clinical applications

    DOE PAGESBeta

    Elzek, Mohamed A.; Rodland, Karin D.

    2015-03-04

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification ofmore » aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.« less

  11. Proteomics of ovarian cancer: functional insights and clinical applications

    SciTech Connect

    Elzek, Mohamed A.; Rodland, Karin D.

    2015-03-04

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. In conclusion, we propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.

  12. Proteomics of ovarian cancer: functional insights and clinical applications

    PubMed Central

    Rodland, Karin D.

    2016-01-01

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. We propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs. PMID:25736266

  13. Proteomics of ovarian cancer: functional insights and clinical applications

    SciTech Connect

    Elzek, Mohamed A.; Rodland, Karin D.

    2015-03-01

    In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicabil- ity of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics’ contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. We propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs.

  14. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells

    PubMed Central

    Gao, Yuxiu; Shan, Ning; Zhao, Cheng; Wang, Yunhai; Xu, Fuliang; Li, Jiacun; Yu, Xiaoqian; Gao, Lifeng; Yi, Zhengjun

    2015-01-01

    Background and Objective: Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin. Methods: SKOV3, OV-90 and SKOV3DDP cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models. Results: LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models. Conclusions: Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients. PMID:26191185

  15. Paclitaxel, Bevacizumab And Adjuvant Intraperitoneal Carboplatin in Treating Patients Who Had Initial Debulking Surgery for Stage II, Stage III, or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2014-06-18

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Primary Peritoneal Cavity Cancer; Stage II Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  16. Breast cancer and ovarian cancer genetics: an update.

    PubMed

    Edlich, Richard F; Cross, Catherine L; Wack, Courtney A; Chase, Margot E; Lin, Kant Y; Long, William B

    2008-01-01

    The purpose of this report on breast cancer and ovarian cancer genetics is to review the evidence for the efficacy of surveillance for early detection, bilateral prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention in preventing breast cancer and improving survival of BRCA1 and BRCA2 carriers. This collective review highlights radiologic screening of patients with this genetic predisposition for cancer as well as discusses cancer risk reduction strategies and reproductive concerns in female BRCA1/2 mutation carriers. It has now been well documented that magnetic resonance imaging (MRI) of the breast has a higher sensitivity than mammography for the diagnosis of breast cancer in patients predisposed to breast cancer. We also emphasize that a new diagnostic device, molecular breast imaging (MBI), is now available and may be as sensitive as MRI. To date, this exciting technology, MBI, has not been used in studies of patients with BRCA1/2 genes. We also discuss in more detail the unique psychological ramifications of female BRCA1/2 mutation carriers. These women face unique choices regarding management of their high risk for breast and ovarian cancer that impact their reproductive options. Despite their high levels of concern, few female BRCA1/2 mutation carriers consider assisted reproduction technologies such as pregnancy surrogate, cryopreservation of oocytes or embryos, or implantation genetic diagnosis to select embryos without BCRA1/2 mutation. Further research must be undertaken to explore the risk management of patients with inherited cancer predisposition and to incorporate these preferences into clinical care. PMID:19105530

  17. MiR-338-3p targets pyruvate kinase M2 and affects cell proliferation and metabolism of ovarian cancer

    PubMed Central

    Zhang, Yuting; Shi, Bing; Chen, Jiang; Hu, Lina; Zhao, Chunquan

    2016-01-01

    MiR-338-3p is down-regulated in cancer, which inhibits cancer cell proliferation, metastasis, and increases chemosensitivity, but its functions in ovarian cancer remains unknown. The present study aims to identify the miR-338-3p targeted genes and to investigate the associated regulatory mechanisms in ovarian cancer cell proliferation and metabolism. Our results demonstrated miR-338-3p expression was down-regulated in most of ovarian cancer tissues and cell lines. Restoration of miR-338-3p expression in ovarian cancer cells could inhibit cell proliferation, lactate production and lactate production of ovarian cancer cells. PKM2 was verified as a target gene of miR-338-3p by luciferase assay. Further study indicated miR-338-3p controlled ovarian cancer cell metabolism by inhibiting PKM2 expression. It is summarized that the regulatory role of miR-338-3p on PKM2 expression in ovarian cancer may play important roles in cell metabolism. PMID:27508048

  18. MiR-338-3p targets pyruvate kinase M2 and affects cell proliferation and metabolism of ovarian cancer.

    PubMed

    Zhang, Yuting; Shi, Bing; Chen, Jiang; Hu, Lina; Zhao, Chunquan

    2016-01-01

    MiR-338-3p is down-regulated in cancer, which inhibits cancer cell proliferation, metastasis, and increases chemosensitivity, but its functions in ovarian cancer remains unknown. The present study aims to identify the miR-338-3p targeted genes and to investigate the associated regulatory mechanisms in ovarian cancer cell proliferation and metabolism. Our results demonstrated miR-338-3p expression was down-regulated in most of ovarian cancer tissues and cell lines. Restoration of miR-338-3p expression in ovarian cancer cells could inhibit cell proliferation, lactate production and lactate production of ovarian cancer cells. PKM2 was verified as a target gene of miR-338-3p by luciferase assay. Further study indicated miR-338-3p controlled ovarian cancer cell metabolism by inhibiting PKM2 expression. It is summarized that the regulatory role of miR-338-3p on PKM2 expression in ovarian cancer may play important roles in cell metabolism. PMID:27508048

  19. Task Force Reaffirms Recommendation against Ovarian Cancer Screening | Division of Cancer Prevention

    Cancer.gov

    Women at average risk of ovarian cancer should not be screened for the disease, the U.S. Preventive Services Task Force (USPSTF) has reaffirmed. Published in the Annals of Internal Medicine on September 11, the latest USPSTF clinical guideline does not apply to women who have symptoms of ovarian cancer or who have genetic mutations that increase their risk of ovarian cancer. |

  20. PTN signaling: Components and mechanistic insights in human ovarian cancer.

    PubMed

    Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W; Godwin, Andrew K

    2015-12-01

    Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

  1. Measurement of Phospholipids May Improve Diagnostic Accuracy in Ovarian Cancer

    PubMed Central

    Davis, Lorelei; Han, Gang; Zhu, Weiwei; Molina, Ashley D.; Arango, Hector; LaPolla, James P.; Hoffman, Mitchell S.; Sellers, Thomas; Kirby, Tyler; Nicosia, Santo V.; Sutphen, Rebecca

    2012-01-01

    Background More than two-thirds of women who undergo surgery for suspected ovarian neoplasm do not have cancer. Our previous results suggest phospholipids as potential biomarkers of ovarian cancer. In this study, we measured the serum levels of multiple phospholipids among women undergoing surgery for suspected ovarian cancer to identify biomarkers that better predict whether an ovarian mass is malignant. Methodology/Principal Findings We obtained serum samples preoperatively from women with suspected ovarian cancer enrolled through a prospective, population-based rapid ascertainment system. Samples were analyzed from all women in whom a diagnosis of epithelial ovarian cancer (EOC) was confirmed and from benign disease cases randomly selected from the remaining (non-EOC) samples. We measured biologically relevant phospholipids using liquid chromatography/electrospray ionization mass spectrometry. We applied a powerful statistical and machine learning approach, Hybrid huberized support vector machine (HH-SVM) to prioritize phospholipids to enter the biomarker models, and used cross-validation to obtain conservative estimates of classification error rates. Results The HH-SVM model using the measurements of specific combinations of phospholipids supplements clinical CA125 measurement and improves diagnostic accuracy. Specifically, the measurement of phospholipids improved sensitivity (identification of cases with preoperative CA125 levels below 35) among two types of cases in which CA125 performance is historically poor - early stage cases and those of mucinous histology. Measurement of phospholipids improved the identification of early stage cases from 65% (based on CA125) to 82%, and mucinous cases from 44% to 88%. Conclusions/Significance Levels of specific serum phospholipids differ between women with ovarian cancer and those with benign conditions. If validated by independent studies in the future, these biomarkers may serve as an adjunct at the time of clinical

  2. Drugs Approved for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for ovarian cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  3. 76 FR 55209 - National Ovarian Cancer Awareness Month, 2011

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-07

    ... Cancer Awareness Month, 2011 By the President of the United States of America A Proclamation Ovarian cancer continues to have one of the highest mortality rates of any cancer, and it is a leading cause of.... (Presidential Sig.) [FR Doc. 2011-22937 Filed 9-6-11; 8:45 am] Billing code 3195-W1-P...

  4. Vitamin A Metabolism is Impaired in Human Ovarian Cancer

    PubMed Central

    Williams, Stephen J.; Cvetkovic, Dusica; Hamilton, Thomas C.

    2009-01-01

    Objectives We have previously reported that loss in expression of a protein considered critical for vitamin A homeostasis, cellular retinol-binding protein 1 (CRBP1), is an early event in ovarian carcinogenesis. The aim of the present study was to determine if loss of vitamin A metabolism also occurs early in ovarian oncogenesis. Methods We assessed CRBP1 expression by immunohistochemistry in ovaries prophylactically removed from women with a genetic risk for ovarian cancer. Furthermore, we investigated the ability of normal, immortalized but nontumorigenic, and tumorigenic human ovarian epithelial cells to synthesize retinoic acid and retinaldehyde when challenged with a physiological dose of retinol, and determined expression levels of the retinoid-related genes, RARα, RXRα, CRABP1, CRABP2, RALDH1 and RALDH2 in these cells. Results Immunohistochemistry revealed loss of CRBP1 expression in potentially preneoplastic lesions in prophylactic oophorectomies. HPLC analysis of vitamin A metabolism showed production of retinoic acid in four independent, normal human ovarian surface epithelial (HOSE) cell culture upon exposure to retinol. However, only one of two SV40-immortalized HOSE cell lines made RA, while none of the ovarian carcinoma cell lines produced detectable RA due to complete loss of RALDH2. Conclusions The impaired conversion of retinol to RA in ovarian cancer cells, and decreased CRBP1 protein expression in prophylactic oophorectomies support our hypothesis that concomitant losses of vitamin A metabolism and CRBP1 expression contribute to ovarian oncogenesis. PMID:19110304

  5. Glycomics Laboratory for the Early Detection of Epithelial Ovarian Cancer | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Ovarian cancer is a silent killer with few early symptoms and advanced disease present at the time of diagnosis. This cancer is the most lethal of all gynecologic malignancies with over 20,000 new cases diagnosed each year. The 5 year survival rates for ovarian cancer dramatically improve when the disease is diagnosed at an early stage. |

  6. The effect of salinomycin on ovarian cancer stem-like cells

    PubMed Central

    Chung, Hyewon; Kim, Yu-Hwan; Kwon, Myoung; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do

    2016-01-01

    Objective The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. Methods The OVCAR3 cell line was cultured under serum-free conditions to produce floating spheres. The CD44+CD117+ cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic-activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44+CD117+ cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44+CD117+ cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44+CD117+ cells. Conclusion The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer. PMID:27462592

  7. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E; Aalfs, Cora M; Meijers-Heijboer, Hanne E J; van Asperen, Christi J; van Roozendaal, K E P; Hoogerbrugge, Nicoline; Collée, J Margriet; Kriege, Mieke; van der Luijt, Rob B; Peock, Susan; Frost, Debra; Ellis, Steve D; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Walker, Lisa; Porteous, Mary E; Kennedy, M John; Pathak, Harsh; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B; Karlan, Beth Y; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A; Beattie, Mary S; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B; Neuhausen, Susan L; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H; Mai, Phuong L; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D P; Gayther, Simon A; Simard, Jacques; Easton, Douglas F; Couch, Fergus J; Chenevix-Trench, Georgia

    2012-04-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

  8. Reliable in vitro studies require appropriate ovarian cancer cell lines.

    PubMed

    Jacob, Francis; Nixdorf, Sheri; Hacker, Neville F; Heinzelmann-Schwarz, Viola A

    2014-01-01

    Ovarian cancer is the fifth most common cause of cancer death in women and the leading cause of death from gynaecological malignancies. Of the 75% women diagnosed with locally advanced or disseminated disease, only 30% will survive five years following treatment. This poor prognosis is due to the following reasons: limited understanding of the tumor origin, unclear initiating events and early developmental stages of ovarian cancer, lack of reliable ovarian cancer-specific biomarkers, and drug resistance in advanced cases. In the past, in vitro studies using cell line models have been an invaluable tool for basic, discovery-driven cancer research. However, numerous issues including misidentification and cross-contamination of cell lines have hindered research efforts. In this study we examined all ovarian cancer cell lines available from cell banks. Hereby, we identified inconsistencies in the reporting, difficulties in the identification of cell origin or clinical data of the donor patients, restricted ethnic and histological type representation, and a lack of tubal and peritoneal cancer cell lines. We recommend that all cell lines should be distributed via official cell banks only with strict guidelines regarding the minimal available information required to improve the quality of ovarian cancer research in future. PMID:24936210

  9. Reliable in vitro studies require appropriate ovarian cancer cell lines

    PubMed Central

    2014-01-01

    Ovarian cancer is the fifth most common cause of cancer death in women and the leading cause of death from gynaecological malignancies. Of the 75% women diagnosed with locally advanced or disseminated disease, only 30% will survive five years following treatment. This poor prognosis is due to the following reasons: limited understanding of the tumor origin, unclear initiating events and early developmental stages of ovarian cancer, lack of reliable ovarian cancer-specific biomarkers, and drug resistance in advanced cases. In the past, in vitro studies using cell line models have been an invaluable tool for basic, discovery-driven cancer research. However, numerous issues including misidentification and cross-contamination of cell lines have hindered research efforts. In this study we examined all ovarian cancer cell lines available from cell banks. Hereby, we identified inconsistencies in the reporting, difficulties in the identification of cell origin or clinical data of the donor patients, restricted ethnic and histological type representation, and a lack of tubal and peritoneal cancer cell lines. We recommend that all cell lines should be distributed via official cell banks only with strict guidelines regarding the minimal available information required to improve the quality of ovarian cancer research in future. PMID:24936210

  10. PGE2-Induced CXCL12 Production and CXCR4 Expression Controls the Accumulation of Human MDSCs in Ovarian Cancer Environment

    PubMed Central

    Obermajer, Nataša; Muthuswamy, Ravikumar; Odunsi, Kunle; Edwards, Robert P.; Kalinski, Pawel

    2016-01-01

    Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. Here, we show that in ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E2 (PGE2), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE2 was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE2 production. Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. Similarly, COX2 inhibition also blocked CXCL12 production in the ovarian cancer environment and its ability to attract MDSCs. Together, our findings elucidate a central role for PGE2 in MDSC accumulation triggered by the CXCL12-CXCR4 pathway, providing a powerful rationale to target PGE2 signaling in ovarian cancer therapy. PMID:22025564

  11. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer

    SciTech Connect

    Whittemore, A.S.; Gong, G.; Itnyre, J.

    1997-03-01

    We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse. 14 refs., 3 figs., 6 tabs.

  12. Ovarian Cancer Proteomic, Phosphoproteomic, and Glycoproteomic Data Released - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) scientists have just released a comprehensive dataset of the proteomic analysis of high grade serous ovarian tumor samples,

  13. DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

    PubMed Central

    Lu, Zhen; Baquero, Maria T; Yang, Hailing; Yang, Maojie; Reger, Albert S; Kim, Choel; Levine, Douglas A; Clarke, Charlotte H; Liao, Warren S-L; Bast Jr, Robert C

    2014-01-01

    DIRAS3 is an imprinted tumor suppressor gene that is downregulated in 60% of human ovarian cancers. Re-expression of DIRAS3 at physiological levels inhibits proliferation, decreases motility, induces autophagy, and regulates tumor dormancy. Functional inhibition of autophagy with choroquine in dormant xenografts that express DIRAS3 significantly delays tumor regrowth after DIRAS3 levels are reduced, suggesting that autophagy sustains dormant ovarian cancer cells. This study documents a newly discovered role for DIRAS3 in forming the autophagosome initiation complex (AIC) that contains BECN1, PIK3C3, PIK3R4, ATG14, and DIRAS3. Participation of BECN1 in the AIC is inhibited by binding of BECN1 homodimers to BCL2. DIRAS3 binds BECN1, disrupting BECN1 homodimers and displacing BCL2. Binding of DIRAS3 to BECN1 increases the association of BECN1 with PIK3C3 and ATG14, facilitating AIC activation. Amino acid starvation of cells induces DIRAS3 expression, reduces BECN1-BCL2 interaction and promotes autophagy, whereas DIRAS3 depletion blocks amino acid starvation-induced autophagy. In primary ovarian cancers, punctate expression of DIRAS3, BECN1, and the autophagic biomarker MAP1LC3 are highly correlated (P < 0.0001), underlining the clinical relevance of these mechanistic studies. Punctate expression of DIRAS3 and MAP1LC3 was detected in only 21–23% of primary ovarian cancers but in 81–84% of tumor nodules found on the peritoneal surface at second-look operations following primary chemotherapy. This reflects a 4-fold increase (P < 0.0001) in autophagy between primary disease and post-treatment recurrence. We suggest that DIRAS3 not only regulates the AIC, but induces autophagy in dormant, nutrient-deprived ovarian cancer cells that remain after conventional chemotherapy, facilitating their survival. PMID:24879154

  14. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer

    NASA Astrophysics Data System (ADS)

    Gao, Xiang; Wang, Bilan; Wei, Xiawei; Men, Ke; Zheng, Fengjin; Zhou, Yingfeng; Zheng, Yu; Gou, Maling; Huang, Meijuan; Guo, Gang; Huang, Ning; Qian, Zhiyong; Wei, Yuquan

    2012-10-01

    Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.

  15. Use of fertility drugs and risk of ovarian cancer

    PubMed Central

    Diergaarde, Brenda; Kurta, Michelle L.

    2014-01-01

    Purpose of review To highlight recent research and insights into the relationship between fertility drug use and ovarian cancer risk. Recent findings Results from two large case-control studies provided further evidence that fertility drug use does not significantly contribute to risk of ovarian cancer among the majority of women when adjusting for known confounding factors. However, questions regarding the effect on certain subgroups, including long-term fertility drug users, women who remain nulligravid after fertility treatment, women with BRCA1 or BRCA2 mutations, and borderline ovarian tumors, still remain. In addition, it may currently just be too early to determine whether there is an association between fertility drug use and ovarian cancer risk given that many of the exposed women are only now beginning to reach the ovarian cancer age range. Summary Whether use of fertility drugs increases the risk of ovarian cancer is an important question that requires further investigation, in particular given the large number of women utilizing fertility treatments. Fortunately, results from recent studies have been mainly reassuring. Large well-designed studies with sufficient follow-up time are needed to further evaluate the effects of fertility treatments within subgroups defined by patient and tumor characteristics. PMID:24752005

  16. Coordinately up-regulated genes in ovarian cancer.

    PubMed

    Hough, C D; Cho, K R; Zonderman, A B; Schwartz, D R; Morin, P J

    2001-05-15

    A better understanding of the molecular circuitry in normal ovarian tissues and in ovarian cancer will likely provide new targets for diagnosis and therapy. Recently, much has been learned about the genes expressed in ovarian cancer through studies with cDNA arrays and serial analysis of gene expression. However, these methods do not allow highly quantitative analysis of gene expression on a large number of specimens. Here, we have used quantitative real-time RT-PCR in a panel of 39 microdissected ovarian carcinomas of various subtypes to systematically analyze the expression of 13 genes, many of which were previously identified as up-regulated in a subset of ovarian cancers by serial analyses of gene expression. The genes analyzed are glutathione peroxidase 3 (GPX3), apolipoprotein J/clusterin, insulin-like growth factor-binding protein 2, epithelial cell adhesion molecule/GA733-2, Kop protease inhibitor, matrix gla protein, tissue inhibitor of metalloproteinase 3, folate receptor 1, S100A2, signal transducer and activator of transcription 1, secretory leukocyte protease inhibitor, apolipoprotein E, and ceruloplasmin. All of the genes were found overexpressed, some at extremely high levels, in the vast majority of ovarian carcinomas irrespective of the subtype. Interestingly, GPX3 was found at much higher levels in tumors with clear cell histology and may represent a biomarker for this subtype. Some of the genes studied here may thus represent targets for early detection ovarian cancer. The gene expression patterns were not associated with age at diagnosis, stage, or K-ras mutation status in ovarian cancer. We find that several genes are coordinately regulated in ovarian cancer, likely representing the fact that many genes are activated as part of common signaling pathways or that extensive cross-talk exists between several pathways in ovarian cancer. A statistical analysis shows that genes commonly up-regulated in ovarian cancer may result from the aberrant

  17. 3 CFR 8551 - Proclamation 8551 of August 31, 2010. National Ovarian Cancer Awareness Month, 2010

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Ovarian Cancer Awareness Month, 2010 8551 Proclamation 8551 Presidential Documents Proclamations Proclamation 8551 of August 31, 2010 Proc. 8551 National Ovarian Cancer Awareness Month, 2010By the President... ovarian cancer, this disease continues to claim more lives than any other gynecologic cancer....

  18. Genetic changes in nonepithelial ovarian cancer.

    PubMed

    Van Nieuwenhuysen, Els; Lambrechts, Sandrina; Lambrechts, Diether; Leunen, Karin; Amant, Frédéric; Vergote, Ignace

    2013-07-01

    Nonepithelial ovarian cancers (OCs), including sex cord-stromal tumors (SCSTs) and germ cell tumors (GCTs), are an uncommon subset of OC, together accounting for 10% of all OCs. The etiology of these tumors remains largely unresolved. It is well established that tumorigenesis is the result of multiple genetic alterations driving a normal cell toward a malignant state. Much effort has been made into researching the molecular mechanisms underlying epithelial OC, but far less is known about the genetic changes in SCSTs and GCTs. Recently, a single point missense mutation (C134W) was found in the FOXL2 gene in approximately 95% of adult-type granulosa cell tumors, suggesting a key role for FOXL2 in these tumors. By contrast, the FOXL2 mutation was not found in the juvenile type. DICER1 somatic missense mutations were found in approximately 60% of Sertoli-Leydig tumors. Ovarian GCTs share many morphological features and a similar pattern of chromosomal alterations with testicular GCTs. In the latter, recent genome-wide association studies have identified seven susceptibility loci near KITLG, SPRY4, UKC2, BAK1, DMRT1, TERT and ATF7IP. All of the susceptibility loci detected thus far are all involved in primordial germ cell function or sex determination. TGF-β/BMP and Wnt/β-catenin signaling was absent in dysgerminomas, but present in yolk sac tumors, suggesting intertumoral heterogeneity. In this article, the authors aim to provide an overview of the current knowledge on the possible molecular changes in SCSTs and GCTs of the ovary. PMID:23875665

  19. Adipose-derived mesenchymal stem cells promote cell proliferation and invasion of epithelial ovarian cancer

    SciTech Connect

    Chu, Yijing; Tang, Huijuan; Guo, Yan; Guo, Jing; Huang, Bangxing; Fang, Fang; Cai, Jing Wang, Zehua

    2015-09-10

    Adipose-derived mesenchymal stem cell (ADSC) is an important component of tumor microenvironment. However, whether ADSCs have a hand in ovarian cancer progression remains unclear. In this study, we investigated the impact of human ADSCs derived from the omentum of normal donors on human epithelial ovarian cancer (EOC) cells in vitro and in vivo. Direct and indirect co-culture models including ADSCs and human EOC cell lines were established and the effects of ADSCs on EOC cell proliferation were evaluated by EdU incorporation and flow cytometry. Transwell migration assays and detection of MMPs were performed to assess the invasion activity of EOC cells in vitro. Mouse models were established by intraperitoneal injection of EOC cells with or without concomitant ADSCs to investigate the role of ADSCs in tumor progression in vivo. We found that ADSCs significantly promoted proliferation and invasion of EOC cells in both direct and indirect co-culture assays. In addition, after co-culture with ADSCs, EOC cells secreted higher levels of matrix metalloproteinases (MMPs), and inhibition of MMP2 and MMP9 partially relieved the tumor-promoting effects of ADSCs in vitro. In mouse xenograft models, we confirmed that ADSCs promoted EOC growth and metastasis and elevated the expression of MMP2 and MMP9. Our findings indicate that omental ADSCs play a promotive role during ovarian cancer progression. - Highlights: • Omental adipose derived stem cells enhanced growth and invasion properties of ovarian cancer cells. • Adipose derived stem cells promoted the growth and metastasis of ovarian cancer in mice models. • Adipose derived stem cells promoted MMPs expression and secretion of ovarian cancer cells. • Elevated MMPs mediated the tumor promoting effects of ADSCs.

  20. ROS Accumulation by PEITC Selectively Kills Ovarian Cancer Cells via UPR-Mediated Apoptosis

    PubMed Central

    Hong, Yoon-Hee; Uddin, Md. Hafiz; Jo, Untek; Kim, Boyun; Song, Jiyoung; Suh, Dong Hoon; Kim, Hee Seung; Song, Yong Sang

    2015-01-01

    Unfolded protein response (UPR) is crucial for both survival and death of mammalian cells, which is regulated by reactive oxygen species (ROS) and nutrient depletion. In this study, we demonstrated the effect of ROS-accumulation, induced by β-phenethyl isothiocyanate (PEITC), on UPR-mediated apoptosis in ovarian cancer cells. We used ovarian cancer cell lines, PA-1 and SKOV-3, with different p53 status (wild- and null-type, respectively). PEITC caused increased ROS-accumulation and inhibited proliferation selectively in ovarian cancer cells, and glutathione (GSH) depletion in SKOV-3. However, PEITC did not cause any effect in normal ovarian epithelial cells and peripheral blood mononuclear cells. After 48 h of PEITC treatment (5 μM), apoptotic cell death was shown to increase significantly in the ovarian cancer cells and not in the normal cells. The key regulator of UPR-mediated apoptosis, CHOP/GADD153 and endoplasmic reticulum resident chaperone BiP/GRP78 were parallely up-regulated with activation of two major sensors of the UPR [PERK and ATF-6 in PA-1; PERK, and IRE1α in SKOV-3) in response to ROS accumulation induced by PEITC (5 μM). ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the effect of PEITC on UPR signatures (P-PERK, IRE1α, CHOP/GADD153, and BiP/GRP78), suggesting the involvement of ROS in UPR-mediated apoptosis. Altogether, PEITC induces UPR-mediated apoptosis in ovarian cancer cells via accumulation of ROS in a cancer-specific manner. PMID:26284193

  1. Local anesthetic bupivacaine induced ovarian and prostate cancer apoptotic cell death and underlying mechanisms in vitro.

    PubMed

    Xuan, Wei; Zhao, Hailin; Hankin, James; Chen, Lin; Yao, Shanglong; Ma, Daqing

    2016-01-01

    Retrospective studies indicate that the use of regional anesthesia can reduce cancer recurrence after surgery which could be due to ranging from immune function preservation to direct molecular mechanisms. This study was to investigate the effects of bupivacaine on ovarian and prostate cancer cell biology and the underlying molecular mechanisms. Cell viability, proliferation and migration of ovarian carcinoma (SKOV-3) and prostate carcinoma (PC-3) were examined following treatment with bupivacaine. Cleaved caspase 3, 8 and 9, and GSK-3β, pGSK-3β(tyr216) and pGSK-3β(ser9) expression were assessed by immunofluorescence. FAS ligand neutralization, caspase and GSK-3 inhibitors and GSK-3β siRNA were applied to further explore underlying mechanisms. Clinically relevant concentrations of bupivacaine reduced cell viability and inhibited cellular proliferation and migration in both cell lines. Caspase 8 and 9 inhibition generated partial cell death reversal in SKOV-3, whilst only caspase 9 was effective in PC-3. Bupivacaine increased the phosphorylation of GSK-3β(Tyr216) in SKOV-3 but without measurable effect in PC3. GSK-3β inhibition and siRNA gene knockdown decreased bupivacaine induced cell death in SKOV-3 but not in PC3. Our data suggests that bupivacaine has direct 'anti-cancer' properties through the activation of intrinsic and extrinsic apoptotic pathways in ovarian cancer but only the intrinsic pathway in prostate cancer. PMID:27195613

  2. Vaccine Therapy With Sargramostim (GM-CSF) in Treating Patients With Her-2 Positive Stage III-IV Breast Cancer or Ovarian Cancer

    ClinicalTrials.gov

    2016-05-02

    HER2-positive Breast Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor

  3. Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B

    PubMed Central

    Lin, Kai-Ti; Yeh, Yu-Ming; Chuang, Chi-Mu; Yang, Scarlett Y.; Chang, Jer-Wei; Sun, Shu-Pin; Wang, Yi-Shiang; Chao, Kuan-Chong; Wang, Lu-Hai

    2015-01-01

    Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer. PMID:25569036

  4. Epacadostat Before Surgery in Treating Patients With Newly Diagnosed Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-03-09

    Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  5. Metabolic phenotyping for monitoring ovarian cancer patients

    PubMed Central

    Ke, Chaofu; Li, Ang; Hou, Yan; Sun, Meng; Yang, Kai; Cheng, Jinlong; Wang, Jingtao; Ge, Tingting; Zhang, Fan; Li, Qiang; Li, Junnan; Wu, Ying; Lou, Ge; Li, Kang

    2016-01-01

    Epithelial ovarian cancer (EOC) is the most deadly of the gynecological cancers. New approaches and better tools for monitoring treatment efficacy and disease progression of EOC are required. In this study, metabolomics using rapid resolution liquid chromatography mass spectrometry was applied to a systematic investigation of metabolic changes in response to advanced EOC, surgery and recurrence. The results revealed considerable metabolic differences between groups. Moreover, 37, 30, and 26 metabolites were identified as potential biomarkers for primary, surgical and recurrent EOC, respectively. Primary EOC was characterized by abnormal lipid metabolism and energy disorders. Oxidative stress and surgical efficacy were clear in the post-operative EOC patients. Recurrent EOC patients showed increased amino acid and lipid metabolism compared with primary EOC patients. After cytoreductive surgery, eight metabolites (e.g. l-kynurenine, retinol, hydroxyphenyllactic acid, 2-octenoic acid) corrected towards levels of the control group, and four (e.g. hydroxyphenyllactic acid, 2-octenoic acid) went back again to primary EOC levels after disease relapse. In conclusion, this study delineated metabolic changes in response to advanced EOC, surgery and recurrence, and identified biomarkers that could facilitate both understanding and monitoring of EOC development and progression. PMID:26996990

  6. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    PubMed Central

    Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G.; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B.; Shvetsov, Yurii B.; Thompson, Pamela J.; Goodman, Marc T.; Wilkens, Lynne R.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Bogdanova, Natalia; Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P.; Kelley, Joseph L.; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Vierkant, Robert A.; Cunningham, Julie M.; Goode, Ellen L.; Fridley, Brooke L.; Southey, Melissa C.; Giles, Graham G.; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A.T.; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A.; Weber, Rachel Palmieri; Schildkraut, Joellen M.; Iversen, Edwin S.; Berchuck, Andrew; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.; Olson, Sara H.; Orlow, Irene; Bandera, Elisa V.; Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla; Massuger, Leon F.A.G.; Kiemeney, Lambertus A.; Aben, Katja K.H.; van Altena, Anne M.; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D.; Cook, Linda S.; Kelemen, Linda E.; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G.; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Whittemore, Alice S.; McLaughlin, John R.; Risch, Harvey A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C.; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B.; Pharoah, Paul D.P.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh

    2016-01-01

    Objective Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID:25528498

  7. Silencing of MICAL-L2 suppresses malignancy of ovarian cancer by inducing mesenchymal-epithelial transition.

    PubMed

    Zhu, Lin-Yan; Zhang, Wen-Ming; Yang, Xiao-Mei; Cui, Lining; Li, Jun; Zhang, Yan-Li; Wang, Ya-Hui; Ao, Jun-Ping; Ma, Ming-Ze; Lu, Huan; Ren, Yuan; Xu, Shao-Hua; Yang, Guang-Dong; Song, Wei-Wei; Wang, Jing-Hao; Zhang, Xiao-Dan; Zhang, Rong; Zhang, Zhi-Gang

    2015-07-10

    Ovarian cancer remains the disease with the highest associated mortality rate of gynecologic malignancy due to cancer metastasis. Rearrangement of actin cytoskeleton by cytoskeleton protein plays a critical role in tumor cell metastasis. MICAL-L2, a member of MICAL family, can interact with actin-binding proteins, regulate actin cross-linking and coordinate the assembly of adherens junctions and tight junctions. However, the roles of MICAL-L2 in tumors and diseases have not been explored. In this study, we found that MICAL-L2 protein is significantly up-regulated in ovarian cancer tissues along with FIGO stage and associated with histologic subgroups of ovarian cancer. Silencing of MICAL-L2 suppressed ovarian cancer cell proliferation, migration and invasion ability. Moreover, silencing of MICAL-L2 prevented nuclear translocation of β-catenin, inhibited canonical wnt/β-catenin signaling and induced the mesenchymal-epithelial transition (MET). Taken together, our data indicated that MICAL-L2 may be an important regulator of epithelial-mesenchymal transition (EMT) in ovarian cancer cells and a new therapeutic target for interventions against ovarian cancer invasion and metastasis. PMID:25864591

  8. Targeted anti-vascular therapies for ovarian cancer: current evidence.

    PubMed

    Hall, M; Gourley, C; McNeish, I; Ledermann, J; Gore, M; Jayson, G; Perren, T; Rustin, G; Kaye, S

    2013-02-01

    Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis. PMID:23385789

  9. Paclitaxel, Polyglutamate Paclitaxel, or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Peritoneal Cancer, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-03-17

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  10. In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

    PubMed Central

    Dunn, Gavin P.; Cheung, Hiu Wing; Agarwalla, Pankaj K.; Thomas, Sapana; Zektser, Yulia; Karst, Alison M.; Boehm, Jesse S.; Weir, Barbara A.; Berlin, Aaron M.; Zou, Lihua; Getz, Gad; Liu, Joyce F.; Hirsch, Michelle; Vazquez, Francisca; Root, David E.; Beroukhim, Rameen; Drapkin, Ronny; Hahn, William C.

    2014-01-01

    High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer. PMID:24385586

  11. Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk.

    PubMed

    McSorley, Meghan A; Alberg, Anthony J; Allen, Diane S; Allen, Naomi E; Brinton, Louise A; Dorgan, Joanne F; Kaaks, Rudolf; Rinaldi, Sabina; Helzlsouer, Kathy J

    2009-08-01

    Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. PMID:19444906

  12. Carboplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-06-21

    High Grade Ovarian Serous Adenocarcinoma; Ovarian Endometrioid Tumor; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  13. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium.

    PubMed

    Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Toyokuni, Shinnya; Hori, Masaru; Kikkawa, Fumitaka

    2016-06-01

    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma‑activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment. PMID:27035127

  14. Molecular Profiling of Clear Cell Ovarian Cancers

    PubMed Central

    Friedlander, Michael L.; Russell, Kenneth; Millis, Sherri; Gatalica, Zoran; Bender, Ryan; Voss, Andreas

    2016-01-01

    Background Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets. Patients and Methods Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis. Results The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%). Conclusions This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical

  15. 1 in 5 Ovarian Cancer Patients Doesn't Get Life-Extending Surgery

    MedlinePlus

    ... medlineplus.gov/news/fullstory_159190.html 1 in 5 Ovarian Cancer Patients Doesn't Get Life-Extending ... extend ovarian cancer patients' lives, but one in five women does not have the procedure, a new ...

  16. Are Birth Control Pills Tied to Decline in Ovarian Cancer Deaths?

    MedlinePlus

    ... Control Pills Tied to Decline in Ovarian Cancer Deaths? Rates down 16 percent in U.S., 8 percent ... WEDNESDAY, Sept. 7, 2016 (HealthDay News) -- Ovarian cancer deaths are down dramatically in many parts of the ...

  17. 1 in 5 Ovarian Cancer Patients Doesn't Get Life-Extending Surgery

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_159190.html 1 in 5 Ovarian Cancer Patients Doesn't Get ... may significantly extend ovarian cancer patients' lives, but one in five women does not have the procedure, ...

  18. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

    PubMed

    Al-Wahab, Zaid; Mert, Ismail; Tebbe, Calvin; Chhina, Jasdeep; Hijaz, Miriana; Morris, Robert T; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R; Rattan, Ramandeep

    2015-05-10

    Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent. PMID:25895126

  19. Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment

    PubMed Central

    Yeung, Tsz-Lun; Leung, Cecilia S.; Li, Fuhai; Wong, Stephen T. C.; Mok, Samuel C.

    2016-01-01

    Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment. PMID:26751490

  20. Local anesthetic bupivacaine induced ovarian and prostate cancer apoptotic cell death and underlying mechanisms in vitro

    PubMed Central

    Xuan, Wei; Zhao, Hailin; Hankin, James; Chen, Lin; Yao, Shanglong; Ma, Daqing

    2016-01-01

    Retrospective studies indicate that the use of regional anesthesia can reduce cancer recurrence after surgery which could be due to ranging from immune function preservation to direct molecular mechanisms. This study was to investigate the effects of bupivacaine on ovarian and prostate cancer cell biology and the underlying molecular mechanisms. Cell viability, proliferation and migration of ovarian carcinoma (SKOV-3) and prostate carcinoma (PC-3) were examined following treatment with bupivacaine. Cleaved caspase 3, 8 and 9, and GSK-3β, pGSK-3βtyr216 and pGSK-3βser9 expression were assessed by immunofluorescence. FAS ligand neutralization, caspase and GSK-3 inhibitors and GSK-3β siRNA were applied to further explore underlying mechanisms. Clinically relevant concentrations of bupivacaine reduced cell viability and inhibited cellular proliferation and migration in both cell lines. Caspase 8 and 9 inhibition generated partial cell death reversal in SKOV-3, whilst only caspase 9 was effective in PC-3. Bupivacaine increased the phosphorylation of GSK-3βTyr216 in SKOV-3 but without measurable effect in PC3. GSK-3β inhibition and siRNA gene knockdown decreased bupivacaine induced cell death in SKOV-3 but not in PC3. Our data suggests that bupivacaine has direct ‘anti-cancer’ properties through the activation of intrinsic and extrinsic apoptotic pathways in ovarian cancer but only the intrinsic pathway in prostate cancer. PMID:27195613

  1. Ovarian cancer treatment in mutation carriers/BRCAness.

    PubMed

    Lorusso, Domenica; Perotto, Stefania

    2016-10-01

    Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5-year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 (BRCA1/2)-mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks, thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse by using non-platinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic

  2. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism

    PubMed Central

    Wang, Zhi-Qiang; Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Guillemette, Chantal; Gobeil, Stéphane; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2015-01-01

    Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target. PMID:26372729

  3. The Chicken Model of Spontaneous Ovarian Cancer

    PubMed Central

    Hawkridge, Adam M.

    2014-01-01

    The chicken is a unique experimental model for studying the spontaneous onset and progression of ovarian cancer (OVC). The prevalence of OVC in chickens can range from 10–35% depending on age, genetic strain, reproductive history, and diet. Furthermore, the chicken presents epidemiological, morphological, and molecular traits that are similar to human OVC making it a relevant experimental model for translation research. Similarities to humans include associated increased risk of OVC with the number of ovulations, common histopathological sub-types including high-grade serous, and molecular-level markers or pathways such as CA-125 expression and p53 mutation frequency. Collectively, the similarities between chicken and human OVC combined with a tightly controlled genetic background and predictable onset window provides an outstanding experimental model for studying the early events and progression of spontaneous OVC tumors under controlled environmental conditions. This review will cover the existing literature on OVC in the chicken and highlight potential opportunities for further exploitation (e.g, biomarkers, prevention, treatment, and genomics). PMID:25130871

  4. Gemcitabine in patients with ovarian cancer.

    PubMed

    Poveda, Andres

    2005-01-01

    Standard first-line treatment of ovarian cancer (OC) consists of platinum-taxane combined chemotherapy. However, this regimen only cures about 25% of women with OC. Phase II studies have shown that platinum-gemcitabine doublet and platinum-taxane-gemcitabine triplet regimens are active first-line chemotherapy in advanced OC, with overall response rates (ORR) above 55%. Several phase III studies of gemcitabine-based doublet and triplet chemotherapy in OC are currently underway. Preliminary data show that these regimens are well-tolerated, with manageable haematological toxicity, and the efficacy results are eagerly awaited. Gemcitabine is also active as second-line monotherapy in women with recurrent OC, and studies combining gemcitabine with paclitaxel, docetaxel, liposomal doxorubicin or topotecan resulted in higher ORR than gemcitabine alone. Gemcitabine-cisplatin and gemcitabine-carboplatin are active in women with platinum-resistant recurrent OC suggesting in vivo synergy between these two classes of drug. These studies show that gemcitabine-based chemotherapy may have an important role as second-line treatment in women with platinum-resistant OC. Gemcitabine combinations are also highly recommended as they avoid the problems of neurotoxicity and alopecia seen with other regimens. In order to respect the quality of life of women with recurrent OC, assessment of prognostic factors is recommended so that the most appropriate chemotherapy can be administered. PMID:16360545

  5. Postoperative abdominopelvic radiation therapy for ovarian cancer

    SciTech Connect

    Goldberg, N.; Peschel, R.E.

    1988-03-01

    From 1963 through 1984, 74 patients with Stage I, II, or III epithelial ovarian cancer who completed a total hysterectomy and debulking procedure and had less than 2 cm residual disease were treated with whole abdominal and pelvic boost radiation therapy (WAP) at Yale-New Haven Hospital. WAP consisted of a whole abdominal dose of 1750 to 2500 cGy (at 100-160 cGy per fraction) and a total pelvic dose of 4000-4600 cGy. Based on stage, amount of residual disease, pathologic type, and grade of tumor, the 74 patients were classified into a favorable group (FG) and an unfavorable group (UG) using the classification scheme developed at the Princess Margaret Hospital (PMH). The actuarial survival at 10 years for the FG patients was 77% (+/- 10%, 95% confidence limits) and for the UG patients was only 7% (+/- 13%). Local control of disease in the abdomen and pelvis was 87% in the FG and only 36% in the UG. Severe long-term complications occurred in 7% of the patients and consisted of small bowel obstruction. Our results strongly indicate that the PMH classification of FG and UG is useful in our patient population in determining which subgroup of patients should be offered WAP.

  6. Better Therapeutic Trials in Ovarian Cancer

    PubMed Central

    2014-01-01

    The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28–29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy. PMID:24627272

  7. Study examines outcomes from surgery to prevent ovarian cancer

    Cancer.gov

    A new study looked at women at high risk of ovarian cancer who had no clinical signs of the disease and who underwent risk-reducing salpingo-oophorectomy (RRSO). The study results showed cancer in the removed tissues of 2.6 percent (25 of 966) of the par

  8. Neoadjuvant chemotherapy in advanced epithelial ovarian cancer: A survival study

    PubMed Central

    Baruah, Upasana; Barmon, Debabrata; Kataki, Amal Chandra; Deka, Pankaj; Hazarika, Munlima; Saikia, Bhargab J.

    2015-01-01

    Context: Patients with advanced ovarian cancer have a poor prognosis in spite of the best possible care. Primary debulking surgery has been the standard of care in advanced ovarian cancer; however, it is associated with high mortality and morbidity rates as shown in various studies. Several studies have discussed the benefit of neoadjuvant chemotherapy in patients with advanced ovarian cancer. Aims: This study aims to evaluate the survival statistics of the patients who have been managed with interval debulking surgery (IDS) from January 2007 to December 2009. Materials and Methods: During the period from January 2007 to December 2009, a retrospective analysis of 104 patients who underwent IDS for stage IIIC or IV advanced epithelial ovarian cancer at our institute were selected for the study. IDS was attempted after three to five courses of chemotherapy with paclitaxal (175 mg/m2 ) and carboplatin (5-6 of area under curve). Overall survival (OS) and progression free survival (PFS) were compared with results of primary debulking study from existing literature. OS and PFS rates were estimated by means of the Kaplan-Meier method. Results were statistically analyzed by IBM SPSS Statistics 19. Results: The median OS was 26 months and the median PFS was 18 months. In multivariate analysis it was found that both OS and PFS was affected by the stage, and extent of debulking. Conclusions: Neoadjuvant chemotherapy, followed by surgical cytoreduction is a promising treatment strategy for the management of advanced epithelial ovarian cancers. PMID:25810573

  9. Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

    PubMed Central

    Toss, Angela; Tomasello, Chiara; Razzaboni, Elisabetta; Contu, Giannina; Grandi, Giovanni; Cagnacci, Angelo; Schilder, Russell J.; Cortesi, Laura

    2015-01-01

    More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making. PMID:26075229

  10. Hereditary ovarian cancer: not only BRCA 1 and 2 genes.

    PubMed

    Toss, Angela; Tomasello, Chiara; Razzaboni, Elisabetta; Contu, Giannina; Grandi, Giovanni; Cagnacci, Angelo; Schilder, Russell J; Cortesi, Laura

    2015-01-01

    More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65-85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making. PMID:26075229

  11. A distinct molecular profile associated with mucinous epithelial ovarian cancer

    PubMed Central

    Heinzelmann-Schwarz, V A; Gardiner-Garden, M; Henshall, S M; Scurry, J P; Scolyer, R A; Smith, A N; Bali, A; Bergh, P Vanden; Baron-Hay, S; Scott, C; Fink, D; Hacker, N F; Sutherland, R L; O'Brien, P M

    2006-01-01

    Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT–PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC. PMID:16508639

  12. Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease | Division of Cancer Prevention

    Cancer.gov

    New results from the NCI-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care. |

  13. Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-κB/mTOR Signaling

    PubMed Central

    Gao, Xiaohua; Liu, Yongbo; Deeb, Dorrah; Arbab, Ali S.; Gautam, Subhash C.

    2014-01-01

    Pristimerin is a quinonemethide triterpenoid that has shown anticancer activity against some cancer types. However, the antitumor effects of pristimerin (PM) in ovarian cancer cells have not been adequately studied. The objective of the present study was to determine the anticancer activity and its mechanism of action in human ovarian carcinoma cell lines. PM strongly inhibited the proliferation of ovarian cancer cells by inducing apoptosis characterized by increased annexin V-binding, cleavage of poly (ADP-ribose) polymerase (PARP-1) and procaspases-3, -8 and -9. Furthermore, PM caused mitochondrial depolarization. Western blot analysis showed inhibition of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-κB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with PM. Treatment with PM also inhibited the expression of NF-κB-regulated antiapoptotic Bcl-2, Bcl-xL, c-IAP1 and survivin. Thus, our data showing potent antiproliferative and apoptosis-inducing activity of PM in ovarian carcinoma cells through the inhibition of AKT/NF-κB/mTOR signaling pathway warrant further investigation of PM for the management of ovarian cancer. PMID:25509983

  14. ARID1A gene mutation in ovarian and endometrial cancers (Review).

    PubMed

    Takeda, Takashi; Banno, Kouji; Okawa, Ryuichiro; Yanokura, Megumi; Iijima, Moito; Irie-Kunitomi, Haruko; Nakamura, Kanako; Iida, Miho; Adachi, Masataka; Umene, Kiyoko; Nogami, Yuya; Masuda, Kenta; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

    2016-02-01

    The AT-rich interacting domain‑containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome‑wide analyses with next‑generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis‑associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis‑associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis‑associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular‑targeted drug can inhibit proliferation of ARID1A‑mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to

  15. ARID1A gene mutation in ovarian and endometrial cancers (Review)

    PubMed Central

    TAKEDA, TAKASHI; BANNO, KOUJI; OKAWA, RYUICHIRO; YANOKURA, MEGUMI; IIJIMA, MOITO; IRIE-KUNITOMI, HARUKO; NAKAMURA, KANAKO; IIDA, MIHO; ADACHI, MASATAKA; UMENE, KIYOKO; NOGAMI, YUYA; MASUDA, KENTA; KOBAYASHI, YUSUKE; TOMINAGA, EIICHIRO; AOKI, DAISUKE

    2016-01-01

    The AT-rich interacting domain-containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome-wide analyses with next-generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis-associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis-associated carcinoma in ovarian cancer and also from atypical endo-metrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis-associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular-targeted drug can inhibit proliferation of ARID1A-mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for

  16. 3 CFR 8853 - Proclamation 8853 of August 31, 2012. National Ovarian Cancer Awareness Month, 2012

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Ovarian Cancer Awareness Month, 2012 8853 Proclamation 8853 Presidential Documents Proclamations Proclamation 8853 of August 31, 2012 Proc. 8853 National Ovarian Cancer Awareness Month, 2012By the President... lives to ovarian cancer. They are mothers and daughters, sisters and grandmothers, community members...

  17. 3 CFR 8703 - Proclamation 8703 of September 1, 2011. National Ovarian Cancer Awareness Month, 2011

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Ovarian Cancer Awareness Month, 2011 8703 Proclamation 8703 Presidential Documents Proclamations Proclamation 8703 of September 1, 2011 Proc. 8703 National Ovarian Cancer Awareness Month, 2011By the President of the United States of America A Proclamation Ovarian cancer continues to have one of the...

  18. 3 CFR 9008 - Proclamation 9008 of August 30, 2013. National Ovarian Cancer Awareness Month, 2013

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Ovarian Cancer Awareness Month, 2013 9008 Proclamation 9008 Presidential Documents Proclamations Proclamation 9008 of August 30, 2013 Proc. 9008 National Ovarian Cancer Awareness Month, 2013By the President... ovarian cancer, and more than half that number of women will die of this disease. During National...

  19. 3 CFR 8407 - Proclamation 8407 of August 31, 2009. National Ovarian Cancer Awareness Month, 2009

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Ovarian Cancer Awareness Month, 2009 8407 Proclamation 8407 Presidential Documents Proclamations Proclamation 8407 of August 31, 2009 Proc. 8407 National Ovarian Cancer Awareness Month, 2009By the President of the United States of America A Proclamation Ovarian cancer remains the leading cause of death...

  20. Thio-glucose bound gold nanoparticles enhance radio-cytotoxic targeting of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Geng, Feng; Song, Kun; Xing, James Z.; Yuan, Cunzhong; Yan, Shi; Yang, Qifeng; Chen, Jie; Kong, Beihua

    2011-07-01

    The treatment of ovarian cancer has traditionally been intractable, and required novel approaches to improve therapeutic efficiency. This paper reports that thio-glucose bound gold nanoparticles (Glu-GNPs) can be used as a sensitizer to enhance ovarian cancer radiotherapy. The human ovarian cancer cells, SK-OV-3, were treated by gold nanoparticles (GNPs) alone, irradiation alone, or GNPs in addition to irradiation. Cell uptake was assayed using inductively coupled plasma atomic emission spectroscopy (ICP-AES), while cytotoxicity induced by radiotherapy was measured using both 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide and clonogenic assays. The presence of reactive oxygen species (ROS) was determined using CM-H2-DCFDA confocal microscopy and cell apoptosis was determined by an Annexin V-FITC/propidium iodide (PI) kit with flow cytometry. The cells treated by Glu-GNPs resulted in an approximate 31% increase in nanoparticle uptake compared to naked GNPs (p < 0.005). Compared to the irradiation alone treatment, the intracellular uptake of Glu-GNPs resulted in increased inhibition of cell proliferation by 30.48% for 90 kVp and 26.88% for 6 MV irradiation. The interaction of x-ray radiation with GNPs induced elevated levels of ROS production, which is one of the mechanisms by which GNPs can enhance radiotherapy on ovarian cancer.

  1. Lanthanum chloride enhances cisplatin-induced apoptosis in ovarian cancer cells.

    PubMed

    Wang, F; Zhu, Y; Fang, S; Li, S; Liu, S

    2016-01-01

    Ovarian cancer begins in an ovary. It is the leading cause of mortality from gynecologic cancer. Cisplatin is an anti-ovarian tumor drug. However, repeated use of cisplatin causes serious resistance. Recently, Lanthanum chloride (LaCl3) was found to inhibit the proliferation and promote the apoptosis in some cancer cells. In this study, we investigated the influence of LaCl3 on cisplatin-induced apoptosis in the ovarian cell line (COC1). Cell-based assays and analysis of cellular ultra structure were used. Result showed that LaCl3 enhanced cisplatin-induced apoptosis in COC1. Furthermore, the application of Cisplatin also altered the expression level of tumor related proteins, such as ERCC1, Ki67, and CDK6. Overall, we determined the inhibitory effect of LaCl3 on the COC1 growth when treated with Cisplatin, which may serve as a basis for the clinical application of LaCl3 in the treatment of ovarian cancer. PMID:27453264

  2. Clear cell ovarian cancer and endometriosis: is there a relationship?

    PubMed Central

    Suzin, Jacek; Obirek, Katarzyna; Sochacka, Amanda; Łoszakiewicz, Marta

    2016-01-01

    Introduction Ovarian clear cell carcinoma is a rare type of ovarian cancer. In recent years, issues of the common genetic origin of endometriosis and ovarian clear cell carcinoma have been raised. Aim of this study Aim of this study was to evaluate the prevalence of this type of cancer, risk factors, prognosis and its potential aetiological association with endometriosis. Material and methods In a retrospective study, we analysed histopathological data of patients operated in the First Department of Gynaecology and Obstetrics (MU, Lodz) due to ovarian cancer in 2004-2014. Among the 394 patients operated on for ovarian cancer, clear cell carcinoma was found in 0.02% (9/394). Menstrual history, parity, comorbidities, data from physical examination, operational protocols and histopathological diagnoses were analysed. Follow-up was obtained from 77.8% of patients. Statistical analysis was performed using Microsoft Excel 2013. Results The mean age of patients at diagnosis was 57.6 years; the BMI in the study group was 27.2; the majority of patients were multiparous (77.8%). Clear cell carcinoma was detected mostly at stage Ia (n = 4). The concentration of Ca125 in the study group had an average of 142.75 U/ml and a median of 69.3 U/ml. The coexistence of endometriosis could not be clinically or histologically confirmed amongst our patients. The most common comorbidity in the study group was hypertension. Conclusions In our clinical material, ovarian clear cell carcinoma is a rare histopathological specimen with a prognostic value comparable to that of serous ovarian cancer. Due to the rarity of this histopathological subtype, proving a cause-and-effect relationship between it and endometriosis can only be elucidated through statistical studies of the entire population. PMID:27582682

  3. Harnessing Pandemonium: The Clinical Implications of Tumor Heterogeneity in Ovarian Cancer

    PubMed Central

    Blagden, Sarah P.

    2015-01-01

    Heterogeneity has emerged as a key feature of ovarian cancer between different ovarian cancer subtypes; within single ovarian cancer subtypes; and within individual patient tumors. At the genomic level, with the advent of ultra-deep sequencing technologies alongside RNA-Seq, epigenomics, and proteomics, the complexity surrounding heterogeneity has deepened. Here, we summarize the emerging understanding of heterogeneity in cancer as a whole and the key discoveries in this area relating to ovarian cancer. We explore the therapeutic limitations and possibilities posed by heterogeneity and how these will influence the future of ovarian cancer treatment and research. PMID:26175968

  4. Butein Shows Cytotoxic Effects and Induces Apoptosis in Human Ovarian Cancer Cells.

    PubMed

    Yang, Pei-Yu; Hu, Dan-Ning; Lin, I-Ching; Liu, Fu-Shing

    2015-01-01

    Butein is a polyphenol, one of the compounds of chalcones, which are flavonoids that are widely biosynthesized in plants, and exhibits different pharmacological activities. Plants containing butein have been used in Chinese traditional medicine. Recently, it has been reported that butein suppresses proliferation and triggers apoptosis in various human cancer cells in vitro and in vivo. The aim of this study was to investigate its pro-apoptotic effect and mechanisms in two cultured human ovarian cancer cells (ES-2 and TOV-21G). The effects of butein on cell viability were assessed by a MTT assay at 3, 10, 30, and 100 μ/M. The apoptotic pathway related factors, including the mitochondrial transmembrane potential (MTP), cytochrome c, caspase cascade, and Bcl-2 family proteins, were examined. MTT assay revealed that butein was cytotoxic to both