scholarly journals NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1339
Author(s):  
Rüdiger Klapdor ◽  
Shuo Wang ◽  
Michael A. Morgan ◽  
Katharina Zimmermann ◽  
Jens Hachenberg ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Gynecological Cancer ◽  
Antigen Receptor ◽  
Ovarian Cancer Cells ◽  
Ovarian Cancer Stem Cells ◽  
Tumor Spread

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.

scholarly journals HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property in an NFκB-dependent way

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Wenxiang Wang ◽  
Yuxia Gao ◽  
Jing Hai ◽  
Jing Yang ◽  
Shufeng Duan
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Drug Sensitivity ◽  
Ovarian Cancer Cells ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Ovarian Cancer Stem Cells

Abstract Increasing evidence shows that cancer stem cells are responsible for drug resistance and relapse of tumors. In breast cancer, human epidermal growth factor receptor 2 (HER2) induces Herceptin resistance by inducing cancer stem cells. In the present study, we explored the effect of HER2 on cancer stem cells induction and drug sensitivity of ovarian cancer cell lines. First, we found that HER2 overexpression (HER2 OE) induced, while HER2 knockdown (HER2 KD) decreased CD44+/CD24− population. Consistently, HER2 expression was closely correlated with the sphere formation efficiency (SFE) of ovarian cancer cells. Second, we found that NFκB inhibition by specific inhibitor JSH23 or siRNA targetting subunit p65 dramatically impaired the induction of ovarian cancer stem cells by HER2, indicating that NFκB mediated HER2-induced ovarian cancer stem cells. Third, we found that HER2 KD significantly attenuated the tumorigenicity of ovarian cancer cells. Further, we found that HER2 inhibition increased drastically the sensitivity of ovarian cancer cells to doxorubicin (DOX) or paclitaxel (PTX). Finally, we examined the correlation between HER2 status and stem cell-related genes expression in human ovarian tumor tissues, and found that expressions of OCT4, COX2, and Nanog were higher in HER2 positive tumors than in HER2 negative tumors. Consistently, the 5-year tumor-free survival rate of HER2 positive patients was dramatically lower than HER2 negative patients. Taken together, our data indicate that HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property.

scholarly journals Potentialization of N-a-tosyl-L-phenylalanine chloromethyl ketone (TPCK) cytotoxic activity by 2-(1-adamantylamino)-6-methylpyridine (AdAMP) in human ovarian cancer cells

2017 ◽  
Vol 88 (6) ◽  
pp. 307-311
Author(s):  
Jacek Sieńko ◽  
Witold Lasek ◽  
Justyna Teliga-Czajkowska ◽  
Roman Smolarczyk ◽  
Krzysztof Czajkowski
Keyword(s):  
Ovarian Cancer ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Chloromethyl Ketone

scholarly journals EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4693 ◽  
Author(s):  
Nina Mallmann-Gottschalk ◽  
Yvonne Sax ◽  
Rainer Kimmig ◽  
Stephan Lang ◽  
Sven Brandau
Keyword(s):  
Ovarian Cancer ◽  
Nk Cells ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Ovarian Cancer Cells ◽  
Antitumoral Activity ◽  
Egfr Tkis

The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune cells, which has important implications for the design of immunotherapies. In this preclinical study, we treated different ovarian cancer cell lines with anti-epidermal growth factor receptor (EGFR) TKIs and co-incubated them with natural killer (NK) cells. We studied treatment-related structural and functional changes on tumor and immune cells in the presence of the anti-EGFR antibody cetuximab and investigated NK-mediated antitumoral activity. We show that long-term exposure of ovarian cancer cells to TKIs leads to reduced responsiveness of intrinsically sensitive cancer cells over time. Inversely, neither long-term treatment with TKIs nor cetuximab could overcome the intrinsic resistance of certain ovarian cancer cells to anti-EGFR agents. Remarkably, tumor cells pretreated with anti-EGFR TKIs showed increased sensitivity towards NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In contrast, the cytokine secretion of NK cells was reduced by TKI sensitization. Our data suggest that sensitization of tumor cells by anti-EGFR TKIs differentially modulates interactions with NK cells. These data have important implications for the design of chemo-immuno combination therapies in this tumor entity.

Cytotoxic Activity of Gallic Acid and Myricetin against Ovarian Cancer Cells by Production of Reactive Oxygen Species

2021 ◽  
Vol 7 (1) ◽  
pp. 7
Author(s):  
Luis Varela-Rodríguez ◽  
Patricia Talamás-Rohana ◽  
Blanca Sánchez-Ramírez ◽  
Verónica Ivonne Hernández-Ramírez ◽  
Hugo Varela-Rodríguez
Keyword(s):  
Ovarian Cancer ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Gallic Acid ◽  
Therapeutic Potential ◽  
Chromatin Condensation ◽  
Vehicle Group ◽  
Ovarian Cancer Cells ◽  
Ros Generation ◽  
In Silico Studies

Some studies demonstrate that gallic acid (GA) and myricetin (MYR) isolated from Rhus trilobata provide the therapeutic activity of this plant against cancer. However, few reports demonstrate that both compounds could also have therapeutic potential in ovarian cancer. Therefore, evaluating the cytotoxic activity of GA and MYR against ovarian cancer cells and determining the possible action mechanism present are important. For this purpose, SKOV-3 cells (ovarian adenocarcinoma; HTB-77™, ATCC®) were cultivated according to the supplier’s instructions (37 °C and 5% CO2) to determine the biological activity of GA and MYR by confocal/transmission electron microscopy, PI-flow cytometry, H2DCF-DA, MTT, and Annexin-V assays. Possible molecular targets of the compounds were determined by the Similarity Ensemble approach. Results showed that GA and MYR treatments decreased the viability of SKOV-3 cells at 50 and 166 μg/mL, respectively (p ≤ 0.05, ANOVA vs. vehicle group). They also induced morphological changes (cytoplasmic reduction, nuclear chromatin condensation, cytoplasmic vesicles increment, polymerized actin, and stabilized tubulin), cell cycle arrest (GA: 8.3% G2/M and MYR: 78% G1), and apoptosis induction (GA: 18.9% and MYR: 8.1%), due to ROS generation (34 to 42%) for 24 h (p ≤ 0.05, ANOVA vs. vehicle group). In silico studies demonstrated that GA and MYR interact with carbonic anhydrase-IX and PI3K, respectively. In conclusion, GA and MYR show cytotoxic activity against SKOV-3 cells through ROS production, which modifies the cytoskeleton and induces apoptosis. Therefore, GA and MYR could be considered as base compounds for the development of new treatments in chemotherapy for ovarian cancer.

Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells

2015 ◽  
Vol 33 (5) ◽  
pp. 1123-1132 ◽  
Author(s):  
Lucie Koubkova ◽  
Rostislav Vyzula ◽  
Jindrich Karban ◽  
Jiri Pinkas ◽  
Eva Ondrouskova ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Mechanism Of Action ◽  
Ovarian Cancer Cells

scholarly journals The Enhanced Efficacy of Intracellular Delivery of Doxorubicin/C6-Ceramide Combination Mediated by the F3 Peptide/Nucleolin System Is Supported by the Downregulation of the PI3K/Akt Pathway

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3052
Author(s):  
Ana F. Cruz ◽  
Mariana B. Caleiras ◽  
Nuno A. Fonseca ◽  
Nélio Gonçalves ◽  
Vera M. Mendes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Intracellular Delivery ◽  
Akt Pathway ◽  
Ovarian Cancer Cells ◽  
Intrinsic Resistance ◽  
Ovarian Cancer Stem Cells ◽  
Ovarian Cancer Cell Lines ◽  
C6 Ceramide

Targeting multiple cellular populations is of high therapeutic relevance for the tackling of solid tumors heterogeneity. Herein, the ability of pegylated and pH-sensitive liposomes, functionalized with the nucleolin-binding F3 peptide and containing doxorubicin (DXR)/C6-ceramide synergistic combination, to target, in vitro, ovarian cancer, including ovarian cancer stem cells (CSC), was assessed. The underlying molecular mechanism of action of the nucleolin-mediated intracellular delivery of C6-ceramide to cancer cells was also explored. The assessment of overexpression of surface nucleolin expression by flow cytometry was critical to dissipate differences identified by Western blot in membrane/cytoplasm of SKOV-3, OVCAR-3 and TOV-112D ovarian cancer cell lines. The former was in line with the significant extent of uptake into (bulk) ovarian cancer cells, relative to non-targeted and non-specific counterparts. This pattern of uptake was recapitulated with putative CSC-enriched ovarian SKOV-3 and OVCAR-3 sub-population (EpCAMhigh/CD44high). Co-encapsulation of DXR:C6-ceramide into F3 peptide-targeted liposomes improved cytotoxic activity relative to liposomes containing DXR alone, in an extent that depended on the intrinsic resistance to DXR and on the incubation time. The enhanced cytotoxicity of the targeted combination was mechanistically supported by the downregulation of PI3K/Akt pathway by C6-ceramide, only among the nucleolin-overexpressing cancer cells presenting a basal p-Akt/total Akt ratio lower than 1.

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