Boosting the apoptotic response of high-grade serous ovarian cancers with CCNE1-amplification to paclitaxel by targeting APC/C and the pro-survival protein MCL-1.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18065-e18065
Author(s):  
Sven Becker ◽  
Klaus Strebhardt ◽  
Ranadip Mandal ◽  
Mourad Sanhaji
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Arrest ◽  
Ovarian Cancer Cells ◽  
Anaphase Promoting Complex ◽  
Ovarian Cancers ◽  
Mitotic Slippage ◽  
Taxane Resistance ◽  
Relevant Dose

e18065 Background: Ovarian cancer exhibits the highest mortality rate among gynecological malignancies. Antimitotic agents, such as paclitaxel, are frontline drugs for the treatment of ovarian cancer. They inhibit microtubule dynamics and their efficiency relies on a prolonged mitotic arrest and the strong activation of the spindle assembly checkpoint (SAC). Although ovarian cancers respond well to paclitaxel, the clinical efficacy is limited due to an early onset of drug resistance, which may rely on a compromised mitosis exit associated with weakend intrinsic apoptosis. Accordingly, we aimed at overcoming SAC silencing that occurs rapidly during paclitaxel-induced mitotic arrest. Methods: To do this, we used a specific anaphase-promoting complex/ cyclosome (APC/C) inhibitor to prevent a premature mitotic exit upon paclitaxel treatment. Furthermore, we investigated the role of the anti-apoptotic BCL-2 family member MCL-1 in determining the fate of ovarian cancer cells with CCNE1-amplification that are challenged with clinically relevant dose of paclitaxel. Results: Using time-laps microscopy we demonstrated that APC/C and MCL-1 inhibition under paclitaxel prevents mitotic slippage in ovarian cancer cells and restores death in mitosis (DIM). Consistent with this, the combinatorial treatment reduced the survival of ovarian cancer cells in 2D and 3D cell models. Since a therapeutic ceiling has been reached with taxanes, it is of utmost importance to develop alternative strategies to improve the patient´s survival. Conclusions: Our study provides not only elements to understand the causes of taxane resistance in CCNE1-amplified ovarian cancers but also suggests a new combinatorial strategy that may improve paclitaxel efficacy in this highly lethal gynecological disease.

scholarly journals Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs

2021 ◽  
Vol 7 (9) ◽  
pp. eabb0737
Author(s):  
Zhengnan Yang ◽  
Wei Wang ◽  
Linjie Zhao ◽  
Xin Wang ◽  
Ryan C. Gimple ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Phenotype ◽  
Ovarian Cancers ◽  
Novel Approach

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

scholarly journals Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability

Neoplasia ◽  
2019 ◽  
Vol 21 (4) ◽  
pp. 363-375 ◽  
Author(s):  
Monika Raab ◽  
Mourad Sanhaji ◽  
Shengtao Zhou ◽  
Franz Rödel ◽  
Ahmed El-Balat ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Chromosomal Instability ◽  
Mitotic Exit ◽  
Ovarian Cancer Cells ◽  
Anaphase Promoting Complex

Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells

2022 ◽  
Author(s):  
Changfa Shu ◽  
Xi Zheng ◽  
Alafate Wuhafu ◽  
Danielle Cicka ◽  
Sean Doyle ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Taxane Resistance ◽  
P53 Inactivation

scholarly journals The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status

2017 ◽  
Vol 43 (5) ◽  
pp. 1755-1766 ◽  
Author(s):  
Mengying Wang ◽  
Yayun Zhang ◽  
Taishu Wang ◽  
Jinrui Zhang ◽  
Zhu Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Pharmacological Intervention ◽  
Ovarian Cancer Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Ovarian Cancers ◽  
Wild Type P53

Background/Aims: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. Methods: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry. To gain mechanistic insights into its effects, immunoblotting was performed to detect USP7, HDM2, p53, p21, apoptosis and autophagy related proteins. Results: P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53. P5091 also prompted autophagy, with more efficient p62 degradation in HeyA8. Conclusion: P5091 shows efficacy in suppressing ovarian cancers harbouring wild-type and mutant p53. Its effects seemed to be enhanced by wild-type p53. The potency of this USP7 inhibitor also correlated with autophagy to some extent. Therefore, the pharmacological targeting of USP7 may serve as a potential therapeutic strategy and warrants further investigation.

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

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Defeng Xu ◽  
Tzu-Hua Lin ◽  
Chiuan-Ren Yeh ◽  
Max A. Cheng ◽  
Lu-Min Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Target Genes ◽  
Ovarian Cancer Cells ◽  
Ovarian Cancer Risk ◽  
Ovarian Cancers ◽  
Practical Strategy ◽  
Er Positive ◽  
Mcf 7

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.

Corilagin Reduces Resistance to PARP Inhibitors by Inhibiting the ERK Signaling Pathway in Ovarian Cancers

2021 ◽  
Author(s):  
Baoxin Luan ◽  
Hongbo Zhao ◽  
Robert C. Bast ◽  
Zhen Lu ◽  
Yinhua Yu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Excision Repair ◽  
Resistant Cell ◽  
Erk Signaling ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Ovarian Cancers ◽  
Resistant Cells

Abstract Background: Corilagin is a compound with hepatoprotective and antiviral activity extracted from Phyllanthus niruri L. Our previous work demonstrated that corilagin inhibits the growth of ovarian cancer cells by regulating the TGF-β/AKT/ERK signaling. Corilagin was also found to sensitize ovarian cancer cells to paclitaxel and carboplatin by inhibiting the Snail-glycolysis pathway. We have now studied whether corilagin could overcome resistance of ovarian cancer cells to poly ADP ribose polymerase inhibitors (PARPi). PARPi block DNA base excision repair and have been approved for treatment of ovarian cancers. Drug resistance has limited efficacy of PARPi. Methods: We have assessed the effect of corilagin alone and in combination with PARPi in two pairs of ovarian cancer cell lines-A2780CP/A2780CP_R and UWB1.289/UWB1.289_R-that are sensitive or resistant to PARPi. CulcuSyn software (BIOSOFT-Software for Science, Cambridge, U.K.) was used to calculate synergy between two drug combinations. Results: Corilagin was active against all four cell lines and enhanced BMN673 activity synergistically in both PARPi resistant cell lines. PARPi-BMN673 down-regulated the expression levels of PARP and up-regulated pH2AX, it decreased pERK activity in sensitive cell lines, but not in resistant cell lines. While corilagin affected DNA repair function to some extent, it inhibited pERK activity in both PARPi sensitive and resistant cells in a dose dependent manner. Corilagin, but not the BMN673, inhibited ZEB1 in resistant cells. Conclusions: Corilagin deserves further evaluation as a drug that could enhance the activity of PARPi in PARPi-resistant ovarian cancer cells.

scholarly journals The apoptotic mechanisms of MT-6, a mitotic arrest inducer, in human ovarian cancer cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Mei-Chuan Chen ◽  
Yi-Chiu Kuo ◽  
Chia-Ming Hsu ◽  
Yi-Lin Chen ◽  
Chien-Chang Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Mitotic Arrest ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer

scholarly journals A Comprehensive Review of the Diagnostic and Treatment Methods for Ovarian Cancer

2018 ◽  
Vol 3 (2) ◽  
pp. 13
Author(s):  
Michelle Davis
Keyword(s):  
Ovarian Cancer ◽  
Iron Oxide ◽  
Cancer Cells ◽  
Iron Oxide Nanoparticles ◽  
Standard Of Care ◽  
Ovarian Cancer Cells ◽  
Oxide Nanoparticles ◽  
Magnetic Iron Oxide Nanoparticles ◽  
Magnetic Iron Oxide ◽  
Ovarian Cancers

Ovarian cancer is amongst the most life-threatening malignancy of the female reproductive system, whereas 90% of those ovarian cancers are epithelial with an overall poor five-year survival rate of 44% across all stages and all races [1]–[2], [31]. This paper aims to review the current treatment and diagnostic strategies for ovarian cancer [3]. Using grounded substantial research, multiple figures were developed to show the relations of ovarian cancer diagnostics and ovarian cancer therapeutics.  It is a great start to look into what may be causing most patients to become resistant to the current standard of care, platinum-based chemotherapeutics, for ovarian cancer [4]. A comprehensive literature review will be used to understand the genetic basis of the disease and possible cancer growth patterns, so we could possibly introduce better diagnostics and therapeutics [5]. The findings show that there are a variety of treatments options other than the standard of care, platinum-based therapy [6]. Nanoparticle encapsulation therapy is one way that has been approved by the FDA to therapeutically treat ovarian cancer without the platinum resistant side effects [7]. Also, the discovery of different diagnostics for ovarian cancer can help with better individualized treatments for patients with different forms of ovarian cancer [8]. Currently, the only serous diagnostic test for the detection of ovarian cancer is high levels of Cancer Antigen 125 (CA-125), which is only shown in 50% of early staged ovarian cancers [16]. The main treatment option for ovarian cancer is platinum-based drugs, in which most cases of patients with ovarian cancer will become resistant. Detecting and treating ovarian cancer while the cells are small, contained, and still in the early stages in vivo still remains to be a challenge [9]. Here, we will demonstrate the bioelectrical interactions of the ovarian cancer cells fused with the magnetic iron oxide nanoparticles with the use of an MRI. The findings demonstrate that the diagnostic method for the early detection of epithelial ovarian cancer requires the use of magnetic iron oxide nanoparticles with specific ligand external profiles as a contrast reagent to make the small-sized ovarian cancer cells appear more visible under MRI. 

scholarly journals Cytokeratin 5–Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer

2015 ◽  
Vol 25 (9) ◽  
pp. 1565-1573 ◽  
Author(s):  
Bradley R. Corr ◽  
Jessica Finlay-Schultz ◽  
Rachel B. Rosen ◽  
Lubna Qamar ◽  
Miriam D. Post ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Cell Populations ◽  
Ovarian Cancers ◽  
Ovarian Cancer Cell Lines ◽  
Cytokeratin 5 ◽  
Induced Apoptosis

ObjectiveCytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+cell populations to cisplatin therapy.Materials and MethodsCytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC50(half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5+cells pretreatment and posttreatment was determined. Proliferation of CK5+versus CK5−cell populations was determined using 5-bromo-2′-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5+versus CK5−cells was measured using immunohistochemical staining for cleaved caspase-3.ResultsCytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5+tumors were also ER+). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER+epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5+compared with CK5−cells were slower proliferating. The prevalence of CK5+cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5+ovarian cancer cells compared with CK5−ovarian cancer cells were more resistant to cisplatin-induced apoptosis.ConclusionsCytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

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