Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer

Abstract Background: ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP).Methods: Our objective was to evaluate the effect of the ONC201 on (1) proliferation, cellular stress, apoptosis and invasion in human serous ovarian cancer (OC) cell lines, and (2) inhibition of tumor growth in a genetically engineered mouse model of high grade serous OC (K18-gT121+/-;p53fl/fl;Brca1fl/fl; KpB) under obese (high fat diet) and lean (low fat diet) conditions. Results: ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. Additionally, ONC201 exhibited greater anti-tumor efficacy in obese (75%) as compared to lean (65%) mice. InterpretationConclusions: These results suggest that ONC206 may be a promising therapeutic agent to be explored in future clinical trials in high grade serous OC.

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Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

SSRN Electronic Journal ◽

10.2139/ssrn.3564375 ◽

2020 ◽

Author(s):

Yali Fan ◽

Jiandong Wang ◽

Ziwei Fang ◽

Stuart R Pierce ◽

Lindsay West ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer

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The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer

Oncotarget ◽

10.18632/oncotarget.8659 ◽

2016 ◽

Vol 7 (26) ◽

pp. 39582-39594 ◽

Cited By ~ 13

Author(s):

Anuj Suri ◽

Xiugui Sheng ◽

Kevin M. Schuler ◽

Yan Zhong ◽

Xiaoyun Han ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Cancer Cells ◽

Genetically Engineered ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer ◽

Genetically Engineered Mouse Model

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A Novel Approach to Identify Genes that Modulate Response of Human Ovarian Cancer Cells to Chemotherapeutic Agents Using High-Throughput RNA Interference

10.21236/ada510407 ◽

2008 ◽

Author(s):

David Azorsa

Keyword(s):

Ovarian Cancer ◽

Rna Interference ◽

Cancer Cells ◽

High Throughput ◽

Chemotherapeutic Agents ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Novel Approach

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Synthetic Naphthoflavonoids Showing Inhibitory Effects on Clonogenicity against Cisplatin-Resistant A2780/Cis Human Ovarian Cancer Cells

Letters in Drug Design & Discovery ◽

10.2174/1570180812666150213230949 ◽

2015 ◽

Vol 12 (8) ◽

pp. 628-639

Author(s):

Yearam Jung ◽

Soon Young Shin ◽

Yeonjoong Yong ◽

Hyuk Yoon ◽

Seunghyun Ahn ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Inhibitory Effects

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Gadolinium Oxide Nanoparticles Enhance the Cytotoxicity of Chemotherapeutic Drugs by Blocking Autophagic Flux in Human Ovarian Cancer Cells

Current Nanoscience ◽

10.2174/1573413716666200313155239 ◽

2020 ◽

Vol 16 ◽

Author(s):

Zhixiong Xie ◽

Tianyu Zhang ◽

Cheng Zhong

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Hela Cells ◽

Late Stage ◽

Ovarian Cancer Cells ◽

Oxide Nanoparticles ◽

Autophagic Flux ◽

Human Ovarian Cancer ◽

Chemotherapeutic Drugs ◽

Chemotherapy Drugs

Background: During chemotherapy, drugs can damage cancer cells’ DNA and cytomembrane structure, and then induce cell death. However, autophagy can increase the chemotherapy resistance of cancer cells, reducing the effect of chemotherapy. Objective: To block the autophagic flux in cancer cells, it is vital to enhance the anti-cancer efficacy of chemotherapy drugs; for this purpose, we test the gadolinium oxide nanoparticles (Gd2O3 NPs)’ effect on autophagy. Methods: The cytotoxicity of Gd2O3 NPs on HeLa cells was evaluated by a (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Then, monodasylcadaverine staining, immunofluorescence, immunoblot and apoptosis assay were conducted to evaluate the effect of Gd2O3 NPs on autophagy and efficacy of chemotherapy drugs in human ovarian cancer cells. Results: We found that Gd2O3 NPs, which have great potential for use as a contrast agent in magnetic resonance imaging, could block the late stage of autophagic flux in a dose-dependent manner and then cause autophagosome accumulation in HeLa cells. When co-treated with 8 μg/mL Gd2O3 NPs and 5 μg/mL cisplatin, the number of dead HeLa cells increased by about 20% compared with cisplatin alone. We observed the same phenomenon in cisplatin-resistant COC1/DDP cells. Conclusion: We conclude that Gd2O3 NPs can block the late stage of autophagic flux and enhance the cytotoxicity of chemotherapeutic drugs in human ovarian cancer cells. Thus, the nanoparticles have significant potential for use in both diagnosis and therapy of solid tumor.

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CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Cancers ◽

10.3390/cancers13112745 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2745

Author(s):

Miran Jeong ◽

Yi-Yue Wang ◽

Ju-Yeon Choi ◽

Myong-Cheol Lim ◽

Jung-Hye Choi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Cancer Cell Invasion ◽

Cc Chemokine ◽

Chemokine Ligand

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

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Long non-coding RNA XIST regulates ovarian cancer progression via modulating miR-335/BCL2L2 axis

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02274-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qingjuan Meng ◽

Ningning Wang ◽

Guanglan Duan

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Invasion And Migration ◽

Non Coding Rna ◽

And Migration ◽

Long Non Coding Rna

Abstract Background X inactivation-specific transcript (XIST) is the long non-coding RNA (lncRNA) related to cancer, which is involved in the development and progression of various types of tumor. However, up to now, the exact role and molecular mechanism of XIST in the progression of ovarian cancer are not clear. We studied the function of XIST in ovarian cancer cells and clinical tumor specimens. Methods RT-qPCR was performed to detect the expression levels of miR-335 and BCL2L2 in ovarian cancer cells and tissues. MTT and transwell assays were carried out to detect cell proliferation, migration, and invasion abilities. Western blot was performed to analyze the expression level of BCL2L2. The interaction between miR-335 and XIST/BCL2L2 was confirmed using a luciferase reporter assay. Results The inhibition of XIST can inhibit the proliferation invasion and migration of human ovarian cancer cells. In addition, the miR-335/BCL2L2 axis was involved in the functions of XIST in ovarian cancer cells. These results suggested that XIST could regulate tumor proliferation and invasion and migration via modulating miR-335/BCL2L2. Conclusion XIST might be a carcinogenic lncRNA in ovarian cancer by regulating miR-335, and it can serve as a therapeutic target in human ovarian cancer.

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