Niclosamide’s potential direct targets in ovarian cancer

Abstract Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. While niclosamide has previously been identified by high-throughput screening platforms as a potential effective compound against several cancer types, no direct binding interactions with distinct biological molecule(s) has been established. The present study identifies key signal transduction mechanisms altered by niclosamide in ovarian cancer. Using affinity purification with a biotin-modified niclosamide derivative and mass spectrometry analysis, several RNA binding proteins were identified. We chose two, FXR1 and IGF2BP2, for further analysis. A significant correlation exists in which high-expression of FXR1 or IGF2BP2 is associated with reduced survival of ovarian cancer patients. Knockdown of FXR1 or IGF2BP2 in ovarian cancer cells resulted in significantly reduced cell viability, adhesion, and migration. Furthermore, FXR1 or IGF2BP2 deficient ovarian cancer cells exhibited reduced response to most doses of niclosamide showing greater cell viability than those with intact RBPs. These results suggest that FXR1 and IGF2BP2 are direct targets of niclosamide and could have critical activities that drive multiple oncogenic pathways in ovarian cancer.

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Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms222111502 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11502

Author(s):

Maria T. Löblein ◽

Isabel Falke ◽

Hans Theodor Eich ◽

Burkhard Greve ◽

Martin Götte ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Ovarian Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Rna Binding ◽

Rna Binding Proteins ◽

Therapy Resistance ◽

Ovarian Cancer Cells

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

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Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:206-210 ◽

2020 ◽

Vol 19 (2) ◽

pp. 206-210

Author(s):

Feng Chen ◽

Bei Zhang

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Protein Kinase ◽

Cell Viability ◽

Cancer Cells ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Ovarian Cancer Cells ◽

Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

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Propofol suppresses cell viability, cell cycle progression and motility and induces cell apoptosis of ovarian cancer cells through suppressing MEK/ERK signaling via targeting circVPS13C/miR-145 axis

Journal of Ovarian Research ◽

10.1186/s13048-021-00775-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Huan Lu ◽

Guanlin Zheng ◽

Xiang Gao ◽

Chanjuan Chen ◽

Min Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Rna Binding ◽

Erk Signaling ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Vacuolar Protein

Abstract Background Propofol is a kind of common intravenous anaesthetic agent that plays an anti-tumor role in a variety of cancers, including ovarian cancer. However, the working mechanism of Propofol in ovarian cancer needs further exploration. Methods The viability and metastasis of ovarian cancer cells were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays. Flow cytometry was used to evaluate the cell cycle and apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the abundance of circular RNA vacuolar protein sorting 13 homolog C (circVPS13C) and microRNA-145 (miR-145). The target relationship between miR-145 and circVPS13C was predicted by circinteractome database and verified by dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot assay was used to detect the levels of phosphorylated extracellular regulated MAP kinase (p-ERK), ERK, p-MAP kinse-ERK kinase (p-MEK) and MEK, in ovarian cancer cells. Results Propofol treatment suppressed the viability, cell cycle and motility and elevated the apoptosis rate of ovarian cancer cells. Propofol up-regulated miR-145 in a dose-dependent manner. Propofol exerted an anti-tumor role partly through up-regulating miR-145. MiR-145 was a direct target of circVPS13C. Propofol suppressed the progression of ovarian cancer through up-regulating miR-145 via suppressing circVPS13C. Propofol functioned through circVPS13C/miR-145/MEK/ERK signaling in ovarian cancer cells. Conclusion Propofol suppressed the proliferation, cell cycle, migration and invasion and induced the apoptosis of ovarian cancer cells through circVPS13C/miR-145/MEK/ERK signaling in vitro.

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

Cancers ◽

10.3390/cancers13081866 ◽

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.

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PLGA-nanoparticles loaded with a thiosemicarbazone derived palladium(ii) complex as a potential agent to new formulations for human ovarian carcinoma treatment

New Journal of Chemistry ◽

10.1039/d0nj00580k ◽

2020 ◽

Vol 44 (35) ◽

pp. 14928-14935

Author(s):

Carolina G. Oliveira ◽

Luciana F. Dalmolin ◽

R. T. C. Silva ◽

Renata F. V. Lopez ◽

Pedro I. S. Maia ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Ovarian Carcinoma ◽

Cancer Cells ◽

Plga Nanoparticles ◽

Cytotoxic Agent ◽

Ovarian Cancer Cells ◽

Ovarian Cell ◽

Encapsulation Process ◽

Human Ovarian Carcinoma

The encapsulation process of the PdII complex [PdCl(PPh3)(PrCh)], a promising cytotoxic agent on ovarian cancer cells, in PLGA polymer was studied. The cytotoxicity results showed that the formulation led to a significant reduction of the ovarian cell viability (80% at 1 μM).

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Anticancer Effects of Cordyceps Militaris Extract in Human Ovarian Cancer Cells via ADORA2B (P05-012-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz030.p05-012-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

So Young Yoon ◽

Soo Jung Park ◽

Yoon Jung Park

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Cordyceps Militaris ◽

Luciferase Reporter ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Camp Production ◽

Anticancer Effects ◽

Sch 58261

Abstract Objectives The study was aimed to determine anticancer effects of Cordyceps militaris extract (CME) and its major bioactive compound, cordycepin, in human ovarian cancer cells, and to identify their putative molecular mechanism mediated by adenosine receptors (ADORAs). Methods CME was prepared in 50% ethanol solution. LC-MS was used for quantification and Q-TOF MS for qualifying bioactive compounds in CME. MTT assay was performed for cell viability in A2780, SKOV-3, TOV112D, and OVCAR-3 human ovarian cancer cell lines. cAMP response element (CRE)-luciferase reporter gene assays were used to determine whether antitumorigenic effect of CME/cordycepin is based on adenosine derivatives. Additionally, the involvement of ADORA signaling pathway was measured using with ADORA2A antagonist SCH 58261 and ADORA2B antagonist PSB 603. Results Cordycepin concentrations of CME was 21.8%. CME was effective to reduce cell viability in A2780 and OVCAR-3 with IC50 115.2 μg/ml and 155.94 μg/ml respectively, while SKOV-3 and TOV112D were relatively resistant to CME. cAMP production was significantly increased by treatment with cordycepin and, lesser extent, with CME. Among the four types of ADORAs, ADORA2A and 2B showed relatively higher expression levels in ovarian cancer cells. The cAMP production by CME was ameliorated by PSB 603, not SCH 58261, treatment. Conclusions CME and cordycepin have anticancer effects in human ovarian cancer cells via ADORA2B-cAMP pathway. Funding Sources NRF of Korea (2017R1D1A1B03034936 & 22A20130012143) and Health Fellowship Foundation.

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ID: 45: EVALUATION OF CELLULAR MECHANISMS BY WHICH CINOBUFOTALIN INHIBITS OVARIAN CANCER CELL LINES FUNCTION

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.77 ◽

2016 ◽

Vol 64 (4) ◽

pp. 950.1-950 ◽

Cited By ~ 1

Author(s):

SH Afroze ◽

DC Zawieja ◽

R Tobin ◽

C Peddaboina ◽

MK Newell-Rogers ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Ovarian Cancer Cells ◽

Ovarian Cancer Cell Lines

ObjectiveCinobufotalin (CINO), a cardiotonic steroid (CTS) or bufadienolide, is extracted from the skin secretions of the traditional Chinese medicine giant toads (Chan su). CINO has been used as a cardiotonic, diuretic and a hemostatic agent. Previously we have shown that CINO inhibits the cytotrophoblast cell function. Recently other study has shown that CINO inhibits A549, a lung cancer cell function. In this study, we assessed the effect of CINO on three different ovarian cancer cell lines; SK-OV-3, CRL-1978 and CRL-11731 to confirm whether the effect of CINO is cell specific.Study DesignWe evaluated the effect of CINO on three ovarian cancer cells SK-OV-3, CRL-1978, and CRL-11731 function in vitro. Each Cell lines were treated with different concentrations of CINO (0.1, 1, 5 and 10 µM). For each cell line cell proliferation, migration and invasion were measured by using a CellTiter Assay (Promega), Cytoselect Assay (Cell Biolabs) and by using a FluoroBlock Assay (BD) respectively. Proliferating Cell Nuclear Antigen (PCNA) was also evaluated in cell lysates of CINO treated these 3 ovarian cancer cells by western blot analysis. Cell Cycle arrest and Cell viability were determined by fluorescence-activated cell sorting (FACS) analysis. We also performed Annexin V staining on CINO treated these 3 ovarian cancer cell lines by immunofluorescence to evaluate the pro-apoptotic protein expression. In addition mitochondrial membrane potential has also been measured for all these 3 ovarian cell lines after CINO treatment using MMP kit, by FACS analysis.ResultsConcentration of CINO at 0.5 µM inhibit SK-OV-3, CRL-1978, and CRL-11731 ovarian cancer cells proliferation, migration and invasion without cell death and loss of cell viability but cell viability differs for each cell line. Each cell lines differ in response to CINO doses for PCNA expression as well as Annexin V pro-apoptotic protein expression. CINO decreases mitochondrial membrane potential for SK-OV-3 but for CRL-1978 and CRL-11731 increases in response to CINO treatment.ConclusionCINO is cell specific, as each cancer cell line responds differently. These data demonstrate that the mode of action of CINO is different on these 3 types of ovarian cancer cells.

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Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms221910255 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10255

Author(s):

Woo Yeon Hwang ◽

Wook Ha Park ◽

Dong Hoon Suh ◽

Kidong Kim ◽

Yong Beom Kim ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Irreversible Inhibitor ◽

Protein Levels ◽

Bax Protein ◽

Apoptotic Effects

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer.

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NDRG2 gene expression pattern in ovarian cancer and its specific roles in inhibiting cancer cell proliferation and suppressing cancer cell apoptosis

10.21203/rs.2.20090/v2 ◽

2020 ◽

Author(s):

Fenhong Kang ◽

Yanlong Wang ◽

Yaping Luo ◽

Yongjun Zhang

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Colony Formation ◽

G1 Phase ◽

Ovarian Cancer Cells ◽

Cycle Arrest

Abstract Background: The cancer cell metastasis and the acquisition of chemotherapy resistance remain huge challenge for ovarian cancer treatment. Previously, N-myc downstream-regulated gene 2 (NDRG2) serves as a tumor suppressor for many cancers. Here, we attempted to investigate the specific roles of NDRG2 in ovarian cancer. Methods: The expression levels of NDRG2 were detected by qRT-PCR or Immunoblotting. CCK-8 assay was employed to examine the cell viability of ovarian cancer cells. The colony formation ability was determined by colony formation assay. Flow cytometry analyses were performed to detect the cell apoptosis and cell cycle. Xenograft tumor assay was performed to detect the in vivo function of NDRG2. Results: We revealed that NDRG2 mRNA expression and protein levels were downregulated within both ovarian cancer tissues and cell lines. The overexpression of NDRG2 dramatically inhibited the cell viability and colony formation and tumor growth, whereas promoted the cell apoptosis, cell cycle arrest in G1 phase within ovarian cancer cells. More importantly, NDRG2 overexpression significantly enhanced the suppressive roles of cisplatin (DDP) in ovarian cancer cell viability. On the contrary, NDRG2 silence exerted opposing effects on ovarian cancer cells. Conclusions: In summary, we provide a solid experimental basis demonstrating the tumor-suppressive effects of NDRG2 in inhibiting the cell proliferation, enhancing the cell apoptosis, eliciting the cell cycle arrest in G1 phase, and promoting the suppressive effects of DDP on the viability of ovarian cancer cells. NDRG2 administration presents a potent adjuvant treatment for ovarian cancer therapy.

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The inhibitory effect of curcumin via fascin suppression through JAK/STAT3 pathway on metastasis and recurrence of ovary cancer cells.

10.21203/rs.3.rs-40272/v3 ◽

2020 ◽

Author(s):

Mi Ju Kim

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Anticancer Activity ◽

Cancer Cells ◽

Short Exposure ◽

Ovarian Cancer Cells ◽

Invasion Assay ◽

Stat3 Pathway ◽

Migration Assay ◽

Ovary Cancer

Abstract Background: fascin is an actin-binding protein and highly expressed in ovarian cancer cells. It is associated with metastasis of cancer and may be a useful prognostic factor. Anticancer activity of curcumin is related to its effect on several signaling mechanisms. Although there have been many reports regarding the anticancer properties of curcumin, its inhibitory effects on migration and invasion of ovarian cancer cells, particularly in the context of fascin expression, have not been reported. The purpose of this study was to investigate the effect of curcumin on fascin expression in ovarian cancer cells and to propose a possible mechanism for the anticancer activity of curcumin through reduced fascin expression. Methods: SKOV3, human epithelial ovary cancer cell line, was cultured with curcumin at various dose and duration. The fascin was quantified using cell viability test and Western blot. To determine the effect of curcumin on the upstream pathway of fascin expression, the signal transducer and activator of transcription 3 (STAT3) was analyzed by sandwich-ELISA. Attachment assay, migration assay and invasion assay were analyzed to approve the change of cellular invasiveness of ovary cancer after curcumin. To determine the morphological changes of ovarian cancer cells by curcumin, immunofluorescence was performed. Results: MTS assays showed that cell viability was different at various concentration of curcumin, and as concentration increased, cell viability tended to decrease. Curcumin appears to suppress fascin expression, even with a minimal concentration and short exposure time. Also, curcumin may suppress fascin expression in ovarian cancer cells through STAT3 downregulation. The attachment assay, migration assay and invasion assay of the ovarian cancer cells exhibited a statistically significant decrease. Immunofluorescence revealed a change of cell shape from a typical form of uninfluenced cells to a more polygonal appearance, with a significant reduction in filopodia formation. Conclusions: Curcumin reduces fascin expression through JAK/STAT3 pathway inhibition, which interferes with the cellular interactions essential for the metastasis and recurrence of ovarian cancer cells. Higher curcumin concentrations and longer exposure times concomitantly decreased fascin expression.

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