scholarly journals Inhibition of MUS81 By siRNA Reverses Resistance to Cisplatin in Human Ovarian Cancer Cell Lines

2021 ◽  
Author(s):  
Emma C. Bourton ◽  
Sheba Adam-Zahir ◽  
Piers N. Plowman ◽  
Hussein Nahidh Al-Ali ◽  
Helen A. Foster ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Resistant Cell ◽  
Wild Type ◽  
Ovarian Cancer Cell Lines ◽  
Sirna Knockdown

Abstract Bacground: Drugs that induce DNA interstrand crosslinks form the mainstay of anticancer treatments for different cancers. These drugs are used to treat ovarian cancer which is the most prevalent gynaecological cancer. Five-year survival rates are approximately 40% and the development of drug resistant disease is an important factor in treatment failure. Methods: In this study a comprehensive evaluation of the expression and function of the site-specific endonuclease MUS81 was conducted. Using quantitative real time PCR analysis and imaging flow cytometry we determined the mRNA and protein expression of MUS81 in three ovarian cancer cell lines and two immortalised human fibroblast cell lines which had been made resistant to cisplatin by chronic exposure. siRNA knockdown of MUS81 was employed to determine the effect on overall cell survival which was assessed using clonogenic assays. Results: In the five cisplatin-resistant cell lines we observed increased MUS81 mRNA expression. In addition MUS81 protein expression in the form of discrete nuclear foci in cells was observed in all cell lines following cisplatin exposure, there being significantly more foci in cisplatin resistant cell lines. siRNA knockdown of MUS81 significantly reduced both mRNA and protein levels in two cell lines (SK-OV-3 and MRC5-SV1 – wild-type and resistant) and critically re-sensitised cisplatin resistant cells to wild-type level, determined by clonogenic assay.Conclusion: MUS81 is central to the development of cisplatin resistance in ovarian cancer cell lines. Inhibition of MUS81 restored drug sensitivity to the cells. MUS81 may be a useful therapeutic target to overcome drug resistance in ovarian and other cancers.

scholarly journals Inhibition of MUS81 by siRNA Reverses Resistance to Cisplatin in Human Ovarian Cancer Cell Lines

2021 ◽  
Author(s):  
Emma Bourton ◽  
Sheba Adam Zahir ◽  
Piers Plowman ◽  
Hussein Al-Ali ◽  
Helen Foster ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Resistant Cell ◽  
Wild Type ◽  
Ovarian Cancer Cell Lines ◽  
Sirna Knockdown

Abstract Purpose: Drugs that induce DNA interstrand crosslinks form the mainstay of anticancer treatments for different cancers. These drugs are used to treat ovarian cancer which is the most prevalent gynaecological cancer. Five-year survival rates are approximately 40% and the development of drug resistant disease is an important factor in treatment failure. Methods: In this study a comprehensive evaluation of the expression and function of the site-specific endonuclease MUS81 was conducted. Using quantitative real time PCR analysis and imaging flow cytometry we determined the mRNA and protein expression of MUS81 in three ovarian cancer cell lines and two immortalised human fibroblast cell lines which had been made resistant to cisplatin by chronic exposure. siRNA knockdown of MUS81 was employed to determine the effect on overall cell survival which was assessed using clonogenic assays. Results: In the five cisplatin-resistant cell lines we observed increased MUS81 mRNA expression. In addition MUS81 protein expression in the form of discrete nuclear foci in cells was observed in all cell lines following cisplatin exposure, there being significantly more foci in cisplatin resistant cell lines. siRNA knockdown of MUS81 significantly reduced both mRNA and protein levels in two cell lines (SK-OV-3 and MRC5-SV1 – wild-type and resistant) and critically re-sensitised cisplatin resistant cells to wild-type level, determined by clonogenic assay. Conclusion: MUS81 is central to the development of cisplatin resistance in ovarian cancer cell lines. Inhibition of MUS81 restored drug sensitivity to the cells. MUS81 may be a useful therapeutic target to overcome drug resistance in ovarian and other cancers.

Effect of simultaneous inhibition of MEK and PI3K/Akt pathways on paclitaxel sensitivity in ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 16046-16046
Author(s):  
J. Kigawa ◽  
W. Kawaguchi ◽  
H. Itamochi ◽  
Y. Kanamori ◽  
T. Oishi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Xenograft Model ◽  
Cancer Cell Lines ◽  
Pi3k Inhibitor ◽  
Ovarian Cancer Cell Lines ◽  
Simultaneous Inhibition

16046 Background: Paclitaxel (PTX) is one of the key drugs for ovarian cancer treatment. PTX activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3’-kinase (PI3K) pathways that lead to cell survival pathways. The purpose of this study was to clarify whether and how the inhibitors of MEK and/or PI3K affect the sensitivity to PTX in ovarian cancer cells. Methods: We treated five ovarian cancer cell lines in combination with PTX and MEK- [PD98059 (PD)] and/or PI3K-inhibitor [LY294002 (LY)] and assessed cell viability, apoptosis, and the expression of phosphorylated (p) MEK and pAkt. The sensitivity of the cell lines to PTX was determined by 3-(4,5- dimethylthiazol-2-yl) -2,5-dyphenyltetrazolium bromide (MTT) assay. The level of protein expression was analyzed by western blot analysis. The drug-induced apoptosis was assessed by Annexin V-FITC staining. Additionally, KOC-2S was injected to intraperitoneal cavity of nude mouse. The effect of combined treatment on the survival in xenograft model was investigated. Results: The levels of pMEK and pAkt protein expression were higher in PTX resistant cell lines (KOC-2S and KFTx) than that in sensitive cell lines (KF, SHIN-3, SK-OV-3). Treatment of PTX induced MEK activation in all five ovarian cancer cell lines. The combination of PTX with either PD or LY led to additive effect on cell growth inhibition. In contrast, synergistic effect was observed in the combination of PTX with PD and LY. Furthermore, apoptotic cells were significantly increased after exposure to PTX and both inhibitors in comparison with other treatment conditions, such as PTX alone, PTX with either PD or LY. The level of pMEK induced by PTX was down-regulated by PD. Interestingly, the level of pAkt was up-regulated by the combination of PTX with PD, which was reduced by LY. Treatment with PTX, PD, and LY prolonged survival in an ovarian cancer xenograft model (p < 0.01). Conclusions: The present study suggests that simultaneous inhibition of MEK and PI3K/Akt pathways enhances the sensitivity to PTX in ovarian cancer. The combination of PTX with MEK- and PI3K-inhibitor may be a new treatment strategy for ovarian cancer. No significant financial relationships to disclose.

scholarly journals The Role of Matrix Gla Protein (MGP) Expression in Paclitaxel and Topotecan Resistant Ovarian Cancer Cell Lines

2018 ◽  
Vol 19 (10) ◽  
pp. 2901 ◽  
Author(s):  
Karolina Sterzyńska ◽  
Andrzej Klejewski ◽  
Karolina Wojtowicz ◽  
Monika Świerczewska ◽  
Małgorzata Andrzejewska ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Matrix Gla Protein ◽  
Cancer Resistance ◽  
Ovarian Cancer Cell Lines

The major cause of ovarian cancer treatment failure in cancer patients is inherent or acquired during treatment drug resistance of cancer. Matrix Gla protein (MGP) is a secreted, non-collagenous extracellular matrix protein involved in inhibition of tissue calcification. Recently, MGP expression was related to cellular differentiation and tumor progression. A detailed MGP expression analysis in sensitive (A2780) and resistant to paclitaxel (PAC) (A2780PR) and topotecan (TOP) (A2780TR) ovarian cancer cell lines and their corresponding media was performed. MGP mRNA level (real time PCR analysis) and protein expression in cell lysates and cell culture medium (Western blot analysis) and protein expression in cancer cells (immunofluorescence analysis) and cancer patient lesions (immunohistochemistry) were determined in this study. We observed increased expression of MGP in PAC and TOP resistant cell lines at both mRNA and protein level. MGP protein was also detected in the corresponding culture media. Finally, we detected expression of MGP protein in ovarian cancer lesions from different histological type of cancer. MGP is an important factor that might contribute to cancer resistance mechanism by augmenting the interaction of cells with ECM components leading to increased resistance of ovarian cancer cells to paclitaxel and topotecan. Expression found in ovarian cancer tissue suggests its possible role in ovarian cancer pathogenesis.

scholarly journals MDR Gene Expression Analysis of Six Drug-Resistant Ovarian Cancer Cell Lines

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Radosław Januchowski ◽  
Karolina Wojtowicz ◽  
Patrycja Sujka-Kordowska ◽  
Małgorzata Andrzejewska ◽  
Maciej Zabel
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Multiple Drug Resistance ◽  
Cancer Cell Lines ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Ovarian Cancer Cell Lines

Ovarian cancer is the leading cause of death among gynaecological malignancies. Multiple drug resistance makes cancer cells insensitive to chemotherapy. In this study, we developed six primary ovarian cancer cell lines (W1MR, W1CR, W1DR, W1VR, W1TR, and W1PR) resistant to drugs such as methotrexate, cisplatin, doxorubicin, vincristine, topotecan, and paclitaxel. A chemosensitivity assay MTT test was performed to assess drug cross-resistance. Quantitative real-time polymerase chain reaction and Western blot were also performed to determine mRNA and protein expression of genes involved in chemoresistance. We observed high cross-resistance to doxorubicin, vincristine, and paclitaxel in the cell lines resistant to these agents. We also found a significant correlation between resistance to these drugs and increased expression of P-gp. Two different mechanisms of topotecan resistance were observed in the W1TR and W1PR cell lines. We did not observe any correlation between MRP2 transcript and protein levels. Cell lines resistant to agents used in ovarian cancer treatment remained sensitive to methotrexate. The main mechanisms of drug resistance were due to P-gp expression in the doxorubicin, vincristine, and paclitaxel resistant cell lines and BCRP expression in the topotecan resistant cell line.

scholarly journals Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines

2014 ◽  
Vol 4 ◽  
Author(s):  
Brittany Anne Davidson ◽  
Jennifer M. Rubatt ◽  
David L. Corcoran ◽  
Deanna K. Teoh ◽  
Marcus Q. Bernardini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Wild Type ◽  
Ovarian Cancer Cell Lines ◽  
Angiogenic Gene

PKC Signaling is Involved in the Regulation of Progranulin (Acrogranin/PC-Cell-Derived Growth Factor/Granulin-Epithelin Precursor) Protein Expression in Human Ovarian Cancer Cell Lines

2012 ◽  
Vol 22 (6) ◽  
pp. 945-950 ◽  
Author(s):  
Laura Diaz-Cueto ◽  
Fabian Arechavaleta-Velasco ◽  
Adriana Diaz-Arizaga ◽  
Pablo Dominguez-Lopez ◽  
Martha Robles-Flores
Keyword(s):  
Ovarian Cancer ◽  
Protein Kinase ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Phosphatidylinositol 3 Kinase ◽  
Ovarian Cancer Cell Lines ◽  
Extracellular Signal

ObjectiveOverexpression of progranulin (also named acrogranin, PC-cell-derived growth factor, or granulin-epithelin precursor) is associated with ovarian cancer, specifically with cell proliferation, malignancy, chemoresistance, and shortened overall survival. The objective of the current study is to identify the signaling pathways involved in the regulation of progranulin expression in ovarian cancer cell lines.MethodsWe studied the relation of protein kinase C (PKC), phosphatidylinositol 3-kinase, protein kinase A, P38, extracellular signal-regulated kinase, and Akt pathways on the modulation of progranulin expression levels in NIH-OVCAR-3 and SK-OV-3 ovarian cancer cell lines. The different pathways were examined using pharmacological inhibitors (calphostin C, LY294002, H89, SB203580, PD98059, and Akt Inhibitor), and mRNA and protein progranulin expression were analyzed by reverse transcriptase polymerase chain reaction and Western blot techniques, respectively.ResultsInhibition of PKC signal transduction pathway by calphostin C decreased in a dose-dependent manner protein but not mRNA levels of progranulin in both ovarian cancer cell lines. LY294002 but not wortmannin, which are phosphatidylinositol 3-kinase inhibitors, also diminished the expression of progranulin in both cell lines. In addition, LY294002 treatment produced a significant reduction in cell viability. Inhibition of protein kinase A, P38, extracellular signal-regulated kinase, and Akt did not affect progranulin protein expression.ConclusionsThese results suggest that the PKC signaling is involved in the regulation of progranulin protein expression in 2 different ovarian cancer cell lines. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the cellular proliferation and invasion in ovarian cancer produced by progranulin.

scholarly journals Hymenialdisine is Cytotoxic against Cisplatin-Sensitive but not against Cisplatin-Resistant Cell Lines

2021 ◽  
Author(s):  
Nada Abdulla ◽  
Najwa Al Balushi ◽  
Syed Imran Hasan ◽  
Shadia Al Bahlani ◽  
Sergey Dobretsov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Resistant Cell ◽  
Marine Sponges ◽  
Ovarian Cancer Cell Lines ◽  
Keywords Ovarian Cancer ◽  
New Compounds

New compounds are needed to overcome the resistance to commonly used cytotoxic chemotherapy for epithelial ovarian cancer. Marine sponges are a rich source of diverse chemical compounds, and hymenialdisine has been found to have antiproliferative effects. We investigated the cytotoxic effect of hymenialdisine in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. Methods: The anti-cancer effects of hymenialdisine or cisplatin were assessed by treating cells with different concentrations of hymenialdisine and cisplatin. Cell viability was determined using the AlamarBlue® Assay. Results: The IC50 of cisplatin was estimated at 31.4 μM for A2780S and 76.9 μM for A2780CP, whereas the IC50 of hymenialdisine was evaluated at 146.8 μM for A2780S cells. Despite the higher concentrations of hymenialdisine (up to 300 μM), IC50 could not be determined for the A2780CP cell line. Conclusion: When compared to cisplatin, hymenialdisine was less toxic against both A2780S and A2780CP ovarian cancer cell lines. Keywords: Ovarian Cancer, Marine compounds, Cisplatin, Hymenialdisine, Oman

scholarly journals Niosome-encapsulated balanocarpol: compound isolation, characterisation, and cytotoxicity evaluation against human breast and ovarian cancer cell lines

2020 ◽  
Vol 31 (19) ◽  
pp. 195101 ◽  
Author(s):  
Mohammad A Obeid ◽  
Siti Aisya S Gany ◽  
Alexander I Gray ◽  
Louise Young ◽  
John O Igoli ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Breast ◽  
Breast And Ovarian Cancer ◽  
Ovarian Cancer Cell Lines
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