STAT3 Inhibitor Napabucasin Inhibits Tumor Growth and Cooperates with Proteasome Inhibition in Human Ovarian Cancer Cells

2021 ◽  
Vol 16 ◽  
Author(s):  
Yao Liu ◽  
Xiaolin Peng ◽  
Hui Li ◽  
Wenhui Jiao ◽  
Xin Peng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Single Agent ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells ◽  
Autophagic Flux ◽  
Antitumor Effects ◽  
Proliferative Effect

Background: Ovarian cancer is a disease with the highest mortality in gynecologic malignancies. Activation of STAT3 pathway is well known to be associated with tumor progression and metastasis in a number of cancers including ovarian cancer. Therefore, STAT3 may be an ideal target for ovarian cancer treatment. Objective: The present study aims to determine the antitumor activity of STAT3 inhibitor Napabucasin as a single agent or in combination with proteasome inhibitor MG-132 in ovarian cancer cells. Methods: MTT was performed to determine the anti-proliferative effect of Napabucasin on ovarian cancer SKOV-3 cells. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. MDC staining and tandem mRFP-GFP-LC3 fluorescence microscopy were used to analyze the autophagy inducing capability of Napabucasin with or without MG-132. The combinational anticancer effect of Napabucasin and MG-132 was evaluated according to Chou and Talalay’s method (1984). Results: Napabucasin showed obvious tumor-inhibitory effects against SKOV-3 cells. Treatment by Napabucasin arrested cell cycle progression in G2/M phase. Mechanistically, elevated expression of p21 may contribute to the blockade of cell cycle. Moreover, we demonstrated that Napabucasin induced autophagy in SKOV-3 cells by using various assays including MDC staining, autophagic flux examination, and detection of the autophagy markers. In addition, combination of Napabucaisin with MG-132 exhibited significant synergistic anti-proliferative effect, probably by inducing apoptosis through a mitochondria-dependent pathway. The two compounds induced pro-survival autophagies, and co-treated with autophagy inhibiter might further enhance their antitumor effects. Conclusion: Napabucasin alone or in combination with MG-132 might be promising treatment strategies for ovarian cancer patients.

Evaluation of GPER agonist G-1 combined with navitoclax in platinum-resistant and -sensitive ovarian cancer cells.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13563-e13563
Author(s):  
Dennis C. DeSimone ◽  
Trung T. Nguyen ◽  
Eugen Brailiou ◽  
John C. Taylor ◽  
Gabriela Cristina Brailoiu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Parp Cleavage ◽  
Ovarian Cancer Cells ◽  
Cycle Progression ◽  
Platinum Based Chemotherapy ◽  
Induced Apoptosis ◽  
In Cells

e13563 Background: Most ovarian cancer patients are treated with platinum-based chemotherapy but eventually relapse with incurable disease. The G protein-coupled estrogen receptor GPER (GPR30) mediates Ca2+ mobilization in response to estrogen and G-1, a synthetic agonist. Large and sustained Ca2+ responses can lead to mitochondrial Ca2+ overload and apoptosis. Hence, we evaluated whether G-1 could induce apoptosis in cisplatin-sensitive A2780 and isogenic cisplatin–resistant CP70 (14-fold resistant), C30 (70-fold resistant) and C200 (157-fold resistant) human ovarian cancer cells. Bcl-2 and Bcl-xL protect mitochondria from Ca2+overload, and were overexpressed in these cisplatin-resistant cells; thus we also examined combining the Bcl-2 family inhibitor navitoclax with G-1. Methods: Cytoplasmic [Ca2+]c and mitochondrial [Ca2+]m were monitored using microscopy and fluorescent Ca2+ probes. Cell cycle, apoptosis and mitochondrial membrane potential (MMP) were assessed by flow cytometry of propidium iodide, Annexin V and DiIC1(5) -stained cells. The intracellular Ca2+ chelator BAPTA was used to block Ca2+mobilization. Results: Expression of the 53kDa GPER but not the 38 kDa isoform progressively increased with increasing cisplatin resistance. G-1 elicited sustained [Ca2+]c rises that correlated with 53 kDa GPER expression, followed by rises in [Ca2+]m. In all cells, 2.5 μM G-1 blocked cell cycle progression at G2/M, inhibited proliferation, and induced apoptosis (A2780 > C30 > CP70 ≥ C200). G-1 induced p53, caspase-3 and PARP cleavage, and MMP loss. BAPTA prevented G-1’s cell cycle and apoptotic effects in cells showing large Ca2+ mobilization responses but did not in cells with small Ca2+responses. Combining navitoclax with G-1 superadditively decreased cell viability and increased apoptosis. Conclusions: G-1 blocked cell cycle progression and induced apoptosis via a Ca2+-dependent pathway in cells expressing high 53 kDa GPER levels, but via a Ca2+-independent pathway in cells with low 53 kDa GPER expression. G-1 also interacted cooperatively with naviticlax. Therefore, G-1 plus navitoclax shows potential for therapeutic use in platinum-sensitive and -resistant ovarian cancer.

Beta-Caryophyllene Suppresses Ovarian Cancer Proliferation by Inducing Cell Cycle Arrest and Apoptosis

2020 ◽  
Vol 20 (13) ◽  
pp. 1530-1537 ◽  
Author(s):  
Santhosh Arul ◽  
Harinee Rajagopalan ◽  
Jivitesh Ravi ◽  
Haripriya Dayalan
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Mtt Assay ◽  
Parp Cleavage ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Proliferative Effect ◽  
Cycle Arrest

Background: Ovarian cancer is the fifth most common cause of cancer deaths among women with lesser prognostics. Current treatment options are chemotherapy with platinum and taxane based chemotherapy. β-Caryophyllene (BCP) an essential oil found in many plant species is known to possess an anti-proliferative effect. Objective: We aimed to investigate the antiproliferative, cytotoxic, and apoptotic role of BCP against ovarian cancer cells PA-1 and OAW 42. Methods: The antiproliferative effect of BCP was determined by MTT assay and cell viability by trypan blue exclusion assay. Cell cycle and live/dead cell analyses were performed by flow cytometry to determine cell cycle distribution and apoptosis, respectively. Results: Results of MTT assay proved the anti-proliferative effect of BCP in a dose and time-dependent manner in ovarian cancer cells. Cell cycle analysis showed that BCP induced S Phase arrest in OAW 42 cells. Results of apoptosis assay confirmed the apoptosis inducing potential of BCP in ovarian cancer cells. The apoptosis is mediated by caspase-3 activation and PARP cleavage. Conclusion: The results of our present study prove that BCP exerts its action partly by inducing cell cycle arrest and apoptosis in ovarian cancer. We conclude that BCP is a potential anti-cancer agent.

scholarly journals A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities

2016 ◽  
Vol 39 (3) ◽  
pp. 871-888 ◽  
Author(s):  
Youlin Deng ◽  
Zhongliang Wang ◽  
Fugui Zhang ◽  
Min Qiao ◽  
Zhengjian Yan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Anticancer Activities ◽  
Cycle Progression ◽  
Igf Signaling

Background/Aims: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells. Methods: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity. Results: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo. Conclusion: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.

scholarly journals 10-Gingerol Inhibits Ovarian Cancer Cell Growth by Inducing G2Arrest

2019 ◽  
Vol 9 (4) ◽  
pp. 685-689 ◽  
Author(s):  
Andrea Rasmussen ◽  
Kaylee Murphy ◽  
David W. Hoskin
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Ovarian Cancer Cell ◽  
Cell Number ◽  
Ovarian Cancer Cells ◽  
Cancer Cell Growth

Purpose: Gingerol homologs found in the rhizomes of ginger plants have the potential to benefithuman health, including the prevention and treatment of cancer. This study evaluated the effectof 10-gingerol on ovarian cancer cell (HEY, OVCAR3, and SKOV-3) growth.Methods: Cell growth was measured by MTT assays, flow cytometry was used to assess cellproliferation, cytotoxicity and cell cycle progression, and western blotting was used to measurecyclin protein expression.Results: Ovarian cancer cells that were treated with 10-gingerol experienced a time- anddose-dependent decrease in cell number, which was due to a reduction in cell proliferationrather than a cytotoxic effect. Reduced proliferation of 10-gingerol-treated ovarian cancercells was associated with an increased percentage of cells in G2 phase of the cell cycle anda corresponding reduction in the percentage of cells in G1. Ovarian cancer cells also showeddecreased cyclin A, B1, and D3 expression following exposure to 10-gingerol.Conclusion: These findings revealed that 10-gingerol caused a G2 arrest-associated suppressionof ovarian cancer cell growth, which may be exploited in the management of ovarian cancer.<br />

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