scholarly journals FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1866
Author(s):  
Katia A. Mesquita ◽  
Reem Ali ◽  
Rachel Doherty ◽  
Michael S. Toss ◽  
Islam Miligy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Nuclear Translocation ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Ovarian Cancer Cells ◽  
Physical Interaction ◽  
Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

scholarly journals Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1028
Author(s):  
Nikolaos Nikoleousakos ◽  
Panagiotis Dalezis ◽  
Aikaterini Polonifi ◽  
Elena G. Geromichalou ◽  
Sofia Sagredou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Positive Control ◽  
Ovarian Cancer Cells ◽  
Antitumor Effects

We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition activity and their DNA damaging effect against human ovarian carcinoma cells. These agents are conjugated with an alkylating component (POPA), which also served as a reference molecule (positive control), and were tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1, UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a standard third-generation PARP inhibitor, on a PARP assay investigating their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression analysis by qRT-PCR was produced in order to measure the absolute and the relative gene expression (in mRNA transcripts) between treated and untreated cells. All the investigated hybrid steroid alkylators and POPA decreased in vitro cell growth differentially, according to the sensitivity and different gene characteristics of each cell line, while ASA-A and ASA-B presented the most significant anticancer activity. Both these compounds induced PARP1/2 enzyme inhibition, DNA damage (alkylation) and upregulation of PARP mRNA expression, for all tested cell lines. However, ASA-C underperformed on average in the above tasks, while the compound ASA-B induced synthetic lethality effects on the ovarian cancer cells. Nevertheless, the overall outcome, leading to a drug-like potential, provides strong evidence toward further evaluation.

Poly-(ADP-ribose) polymerase inhibitors: paradigm shift in the first-line treatment of newly diagnosed advanced ovarian cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 721-727
Author(s):  
Fady Gh Haddad ◽  
Elias Karam ◽  
Elissar Moujaess ◽  
Hampig Raphael Kourie
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Excision Repair ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
First Line ◽  
Free Survival ◽  
Base Excision ◽  
Breast Cancer Gene

Debulking surgery associated with chemotherapy represent the backbone of ovarian cancer therapy. Adding bevacizumab has improved survival. Recently, PARP inhibitors were added in the first line as maintenance treatment for the patients who achieve a complete or partial response. These drugs act by blocking the activity of the PARP enzyme responsible for base-excision repair, and have shown positive responses when used for tumors lacking homologous recombination. Olaparib, niraparib and veliparib were evaluated and showed an increase in the duration of progression-free survival: 22.1 months (hazard ratio [HR] = 0.59), 13.8 (HR = 0.62) and 23.5 (HR = 0.68) with olaparib, niraparib and veliparib, respectively. This review describes the benefit of PARP inhibitors as maintenance therapy and discusses the efficacy according to breast cancer gene and homologous recombination status.

Combinatorial inhibition of Polo-like kinase 1 (PLK1) and microtubule dynamics to induce synthetic lethality in ovarian cancer cells with CCNE1-amplification.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e17537-e17537 ◽  
Author(s):  
Sven Becker ◽  
Monika Raab ◽  
Yves Matthes ◽  
Mourad Sanhaji ◽  
Andrea Krämer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Microtubule Dynamics ◽  
Ovarian Cancer Cells

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

scholarly journals Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yali Fan ◽  
Quanmei Sun ◽  
Xia Li ◽  
Jiantao Feng ◽  
Zhuo Ao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Substrate Stiffness ◽  
Ovarian Cancer Cells ◽  
Physical Parameters ◽  
Chemotherapeutic Drugs ◽  
Multidrug Resistance Proteins ◽  
Mesenchymal Transition ◽  
Growth Phenotype

Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young’s modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.

scholarly journals Non-Phosphorylatable PEA-15 Sensitises SKOV-3 Ovarian Cancer Cells to Cisplatin

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 515 ◽  
Author(s):  
Shahana Dilruba ◽  
Alessia Grondana ◽  
Anke C. Schiedel ◽  
Naoto T. Ueno ◽  
Chandra Bartholomeusz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Antioxidant Response ◽  
The Cancer Genome Atlas ◽  
Favourable Effect ◽  
Ovarian Cancer Cells ◽  
Related Factor ◽  
Potential Candidate ◽  
Cisplatin Sensitivity

The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy.

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells

2020 ◽  
pp. 173817
Author(s):  
Shiwen Xu ◽  
Chunyan Yu ◽  
Xiaoxia Ma ◽  
Yan Li ◽  
Yangyang Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Ovarian Cancer Cells

Wnt5a as a Predictor in Poor Clinical Outcome of Patients and a Mediator in Chemoresistance of Ovarian Cancer

2011 ◽  
Vol 21 (2) ◽  
pp. 280-288 ◽  
Author(s):  
Chunjie Peng ◽  
Xiaolei Zhang ◽  
Hongli Yu ◽  
Donglai Wu ◽  
Jianhua Zheng
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Progression Free Survival ◽  
Prognostic Indicator ◽  
Benign Tumors ◽  
Ovarian Cancer Cells ◽  
Wnt5a Expression ◽  
Gynecology And Obstetrics ◽  
Wide Range

Introduction:Wnt5a regulates numerous signaling pathways controlling a wide range of cellular processes, including cell proliferation, differentiation, and apoptosis. However, it is still unclear whether Wnt5a is involved in mediating chemoresistance in cancer. We studied the correlation of Wnt5a expression with clinicopathologic parameters and survival in epithelial ovarian cancer and the effect of Wnt5a expression on chemoresistance of ovarian cancer cells.Methods:Wnt5a expression was immunohistochemically examined in ovarian cancer, benign tumor, and normal ovarian tissues. Two stable cell lines were established, namely, SKOV3/Wnt5a, which overexpressed Wnt5a, and SKOV3/miRNA, which downregulated Wnt5a expression using microRNA (miRNA). Wnt5a expression level was evaluated by semiquantitative reverse transcription-polymerase chain reaction, Western blot analysis, and immunofluorescence assay. The sensitivity of all transfected and untransfected cell lines to chemotherapeutic drugs (paclitaxel, oxaliplatin, 5-fluorouracil, epirubicin, and etoposide) was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay.Results:Wnt5a was found to be significantly higher in ovarian cancer compared with benign tumors and normal ovaries. High levels of Wnt5a expression were associated with the International Federation of Gynecology and Obstetrics stage and significantly predicted a poorer overall survival and progression-free survival compared with low Wnt5a expression. In addition, Wnt5a overexpression in SKOV3/Wnt5a cells decreased chemosensitivity compared with normal and empty vector controls (P < 0.05). Alternatively, Wnt5a down-regulation in SKOV3/miRNA cells led to a significant increase in chemosensitivity (P < 0.05).Conclusions:Wnt5a immunoreactivity may be a useful prognostic indicator in patients with ovarian cancer. These results clarified for the first time the possibility that Wnt5a plays an important role in regulating chemosensitivity to anticancer drugs in ovarian cancer cells.

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