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Invasive ovarian tumor platinum resistance

Ali R Özeş, Yinu Wang, Xingyue Zong, Fang Fang, Jay Pilrose, Kenneth P Nephew
Long non-coding RNAs (lncRNAs) play key roles in human diseases, including cancer. Functional studies of the lncRNA HOTAIR (HOX transcript antisense RNA) provide compelling evidence for therapeutic targeting of HOTAIR in cancer, but targeting lncRNAs in vivo has proven to be difficult. In the current study, we describe a peptide nucleic acids (PNA)-based approach to block the ability of HOTAIR to interact with EZH2 and subsequently inhibit HOTAIR-EZH2 activity and resensitize resistant ovarian tumors to platinum...
April 18, 2017: Scientific Reports
Jennifer M Scalici, Sanja Arapovic, Erin J Saks, Kristen A Atkins, Gina Petroni, Linda R Duska, Jill K Slack-Davis
BACKGROUND: Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. METHODS: A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens...
May 15, 2017: Cancer
Maria R Amoroso, Danilo S Matassa, Ilenia Agliarulo, Rosario Avolio, Haonan Lu, Lorenza Sisinni, Giacomo Lettini, Hani Gabra, Matteo Landriscina, Franca Esposito
Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC...
December 15, 2016: Cell Death & Disease
Zhentong Wei, Yan Liu, Yishu Wang, Yandong Zhang, Qinghua Luo, Xiaxia Man, Feng Wei, Xiaowei Yu
Ovarian cancer (OVCa) stem cells are associated with tumor growth, metastasis, and recurrence, which are driving forces behind a majority of the OVCa-related mortality. This subpopulation of cancer cells are characterized by uncontrolled proliferation, high invasiveness, and resistance against the current platinum-based therapy. Thus, targeting OVCa cancer stem cells has been focused in recent therapeutic development. Isolation and purification of cancer stem cells are, however, challenging for the lack of sensitive and specific markers...
November 2016: Medical Oncology
Bin Ai, Zhixin Bie, Shuai Zhang, Ailing Li
Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer...
2016: American Journal of Cancer Research
Adam C ElNaggar, Uksha Saini, Shan Naidu, Ross Wanner, Millie Sudhakar, John Fowler, Masaki Nagane, Periannan Kuppusamy, David E Cohn, Karuppaiyah Selvendiran
We have previously developed a novel class of bi-functional compounds based on a diarylidenyl-piperidone (DAP) backbone conjugated to an N-hydroxypyrroline (-NOH; a nitroxide precursor) group capable of selectively inhibiting STAT3 activation, translocation, and DNA binding activity. HO-4200 and H-4318 are 2 such derivatives capable of inducing apoptosis in ovarian cancer cells through this mechanism and demonstrated efficacy in platinum resistant primary ovarian cancer cell populations and tumor tissues. The improved absorption and cellular uptake of HO-4200 by cancer cells was determined using optical and electron paramagnetic resonance spectrometry...
October 2, 2016: Cancer Biology & Therapy
U Saini, S Naidu, A C ElNaggar, H K Bid, J J Wallbillich, K Bixel, C Bolyard, A A Suarez, B Kaur, P Kuppusamy, J Hays, P J Goodfellow, D E Cohn, K Selvendiran
Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases...
January 12, 2017: Oncogene
Snider Desir, Elizabeth L Dickson, Rachel I Vogel, Venugopal Thayanithy, Phillip Wong, Deanna Teoh, Melissa A Geller, Clifford J Steer, Subbaya Subramanian, Emil Lou
In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200).We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment...
July 12, 2016: Oncotarget
Canan Schumann, Stephanie Chan, Oleh Khalimonchuk, Shannon Khal, Vitaliya Moskal, Vidhi Shah, Adam W G Alani, Olena Taratula, Oleh Taratula
We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress, and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells...
June 6, 2016: Molecular Pharmaceutics
Houshan Yao, Chang Sun, Zhiqian Hu, Weijun Wang
Annexin A4 (ANXA4) is a member of the annexin family that binds to both calcium ions and phospholipids. Studies indicate that ANXA4 modulates membrane permeability and membrane trafficking, participates in cellular growth and apoptosis, enhances tumor invasion and promotes anti-tumor drug resistance. The overexpression of ANXA4 has been identified in various clinical epithelial tumors including: lung, gastric, colorectal, pancreatic, gallbladder, breast, renal, ovarian, laryngeal, and prostate cancers. In addition, upregulation and nuclear translocation of ANXA4 have been observed in the progression of colorectal cancer and ovarian serous carcinoma...
2016: Frontiers in Bioscience (Landmark Edition)
Jing Zhang, Lei Liu, Yunyan Sun, Jiandong Xiang, Dongmei Zhou, Li Wang, Huali Xu, Xiaoming Yang, Na Du, Meng Zhang, Qin Yan, Xiaowei Xi
The lack of efficient tumor progression and chemoresistance indicators leads to high mortality in epithelial ovarian cancer (EOC) patients. Dysregulated miR-520g expression is involved in these processes in hepatic and colorectal cancers. In this study, we found that miR-520g expression gradually increased across normal, benign, borderline and EOC tissues. High miR-520g expression promoted tumor progression and chemoresistance to platinum-based chemotherapy, and reduced survival in EOC patients. miR-520g upregulation increased EOC cell proliferation, induced cell cycle transition and promoted cell invasion, while miR-520g downregulation inhibited tumor-related functions...
May 3, 2016: Oncotarget
Arpita Kulshrestha, Gajendra K Katara, Jordyn Ginter, Sahithi Pamarthy, Safaa A Ibrahim, Mukesh K Jaiswal, Corina Sandulescu, Ramayee Periakaruppan, James Dolan, Alice Gilman-Sachs, Kenneth D Beaman
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...
June 2016: Molecular Oncology
Ranganatha R Somasagara, Kaushlendra Tripathi, Sebastian M Spencer, David W Clark, Reagan Barnett, Lavanya Bachaboina, Jennifer Scalici, Rodney P Rocconi, Gary A Piazza, Komaraiah Palle
Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression...
January 15, 2016: Biochemical and Biophysical Research Communications
Rosanna Sestito, Roberta Cianfrocca, Laura Rosanò, Piera Tocci, Elisa Semprucci, Valeriana Di Castro, Valentina Caprara, Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino, Anna Bagnato
Drug resistance remains the major clinical barrier to successful treatment in epithelial ovarian carcinoma (EOC) patients, and the evidence of microRNA involvement in drug resistance has been recently emerging. Endothelin-1 (ET-1)/ETA receptor (ETAR) axis is aberrantly activated in chemoresistant EOC cells and elicits pleiotropic effects promoting epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance. However, the relationship between ETAR and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ETAR expression in sensitive and resistant EOC cells...
January 26, 2016: Oncotarget
Hiroshi Katagiri, Kentaro Nakayama, Sultana Razia, Kohei Nakamura, Emi Sato, Tomoka Ishibashi, Masako Ishikawa, Kouji Iida, Noriyoshi Ishikawa, Yoshiro Otsuki, Satoru Nakayama, Satoru Kyo
The aim of the present study was to clarify the role of autophagy in cisplatin (CDDP) sensitivity in OCCCs and the role of Beclin 1 in OCCC progression. Autophagy was measured using: i) western blot analysis of LC3 and p62 and ii) microscopic observation of GFP-LC3 puncta. Autophagy was suppressed using chloroquine and Beclin 1 siRNA. Surgical specimens were examined for Beclin 1 protein expression by immunohistochemistry. The correlations between the loss of Beclin 1 expression and clinicopathological characteristics, prognosis and chemosensitivity were investigated...
December 2015: International Journal of Oncology
E Ciamporcero, H Shen, S Ramakrishnan, S Yu Ku, S Chintala, L Shen, R Adelaiye, K M Miles, C Ullio, S Pizzimenti, M Daga, G Azabdaftari, K Attwood, C Johnson, J Zhang, G Barrera, R Pili
Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer...
March 24, 2016: Oncogene
Marek Cybulski, Bożena Jarosz, Andrzej Nowakowski, Witold Jeleniewicz, Elżbieta Kutarska, Wiesława Bednarek, Andrzej Stepulak
BACKGROUND: Cyclin A is a cell-cycle regulatory gene and its overexpression promotes tumor cell growth. Y-Box-binding protein 1 (YB1) is a transcription/translation factor involved in tumor growth, invasion, and drug resistance. We investigated whether an association exists between protein products of these genes in epithelial ovarian cancer (EOC) specimens and clinicopathological parameters, patient response and EOC sensitivity to platinum-based first-line chemotherapy. PATIENTS AND METHODS: Cyclin A and YB1 expression were analyzed by immunohistochemistry in 54 human primary EOC tissues...
March 2015: Anticancer Research
Marc A Becker, Paul Haluska, Laurie K Bale, Claus Oxvig, Cheryl A Conover
The majority of ovarian cancer patients acquire resistance to standard platinum chemotherapy and novel therapies to reduce tumor burden and ascites accumulation are needed. Pregnancy-associated plasma protein-A (PAPP-A) plays a key role in promoting insulin-like growth factor (IGF) pathway activity, which directly correlates to ovarian cancer cell transformation, growth, and invasiveness. Herein, we evaluate PAPP-A expression in tumors and ascites of women with ovarian cancer, and determine the antitumor efficacy of a neutralizing monoclonal PAPP-A antibody (mAb-PA) in ovarian cancer using primary patient ovarian tumorgrafts ("Ovatars")...
April 2015: Molecular Cancer Therapeutics
Henan Zhao, Sha Liu, Guang Wang, Xian Wu, Yanfang Ding, Gordon Guo, Jiyong Jiang, Shiying Cui
MicroRNAs (miRNAs) are involved in regulating the response of cancer cells to various therapeutic interventions, yet their involvement in the chemoresistance of human epithelial ovarian cancer is not fully understood. We found that miR-136 was significantly downregulated in specimens from patients with chemoresistant epithelial ovarian cancer. In the present study, we aimed to clarify the role of miR-136 in regulating the chemoresistance of ovarian cancer. Thirty-four tumor bank specimens and 2 well-established human ovarian cancer cell lines, C13 and OV2008, were used...
February 2015: Oncology Reports
Yehuda G Assaraf, Christopher P Leamon, Joseph A Reddy
Conventional cancer treatment modalities have several limitations including lack of sufficient efficacy, serious untoward toxicity, as well as innate and acquired drug resistance. In contrast, targeted imaging agents can identify patients with receptors overexpressed on the surface of cancer cells, thus allowing appropriate selection of patients for personalized treatment with a desirable targeted therapeutic. The folate receptor (FR) has been identified as a new molecularly targeted entity, which is highly overexpressed on the surface of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain, endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, head and neck, breast, and non-small cell lung cancer...
October 2014: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
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