Therapeutic Effects of Punicalagin Against Ovarian Carcinoma Cells in Association With β-Catenin Signaling Inhibition

AimThe aim of this study was to investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human A2780 ovarian cancer cells in vitro.MethodsThe viability of human A2780 ovarian cells was evaluated using Cell Counting Kit-8 assay. Cell cycle was detected with flow cytometry analysis. The protein expression levels of Bcl-2, Bax, β-catenin, cyclin D1, survivin, tissue inhibitor of metalloproteinase (TIMP)-2, and TIMP-3 were measured using Western blot analysis. Matrix metalloproteinase (MMP)-2 and MMP-9 activity was determined with gelatin zymography. Wound healing assay was used to determine cell migration.ResultsPunicalagin inhibited the cell viability of A2780 cells in a dose- and time-dependent manner, and the cell cycle of A2780 cells was arrested in G1/S phase transition. The treatment also induced apoptosis as shown by the up-regulation of Bax and down-regulation of Bcl-2. On the other hand, punicalagin treatment increased the expressions of TIMP-2 and TIMP-3, decreased the activities of MMP-2 and MMP-9, and inhibited cell migration. In addition, the β-catenin pathway was suppressed as shown by the down-regulations of β-catenin and its downstream factors including cyclin D1 and survivin.ConclusionsPunicalagin may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against human ovarian cancer in humans through the inhibition of β-catenin signaling pathway.

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Purified Vitexin Compound 1 Serves as a Promising Antineoplastic Agent in Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.734708 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kewen Ma ◽

Kuansong Wang ◽

Yingjun Zhou ◽

Nian Liu ◽

Wei Guo ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Antineoplastic Agent ◽

Chinese Herb ◽

Ovarian Cancer Cells ◽

Therapeutic Effects ◽

Dependent Manner ◽

M Phase

Ovarian cancer is a common gynecologic aggressive neoplasm. The mortality of ovarian cancer is top among gynecologic malignancies due to the insidious onset, atypical early symptoms, and chemoresistance. Therefore, it is urgent to seek another promising treatment for ovarian cancer. Purified vitexin compound 1 (VB1) is a kind of neolignan from the seed of traditional Chinese herb vitex negundo that possessed diverse pharmacological effects. VB1 can exhibit anti-neoplastic activities against various cancers. However, the role of VB1 in ovarian cancer treatment has not been elaborated, and the mechanism is unknown. The aim of this study was to investigate the therapeutic effects of VB1 in ovarian cancer cells both in vitro and in vivo, along with the molecular mechanism of action. In vitro, VB-1 can effectively suppress the proliferation, induce apoptosis, and block cell cycle at G2/M phase with a concentration dependent manner in ovarian cancer cells. Western blot assay showed that VB1 induce apoptosis via upregulating expression of cleaved-caspase3 and block cell cycle at G2/M phase through upregulating expression of P21. Meanwhile, VB1 can effectively inhibit tumor growth in xenograft mouse model. Our research indicated that VB1 can significantly exert its anti-neoplastic effects and may represent a new class of agents in ovarian cancer therapy.

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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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Evaluation of Silibinin-Loaded Microbubbles Combined with Ultrasound in Ovarian Cancer Cells: Cytotoxicity and Mechanisms

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210608101649 ◽

2021 ◽

Vol 21 ◽

Author(s):

Liguang Zhou ◽

Jing Liu ◽

Wen Meng ◽

Huawei Zhang ◽

Bo Chen

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Mechanical Vibration ◽

Cell Types ◽

Local Drug Delivery ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Western Blots

Background: The anticancer activity of silibinin (SB) has been demonstrated in various cancer cell types. However, its low solubility and poor bioavailability limit its clinical potential in biomedical applications. Microbubbles in combination with ultrasound are promising vehicles for local drug delivery. Objective: The present study determined the antitumour effects and molecular mechanism of silibinin-loaded microbubbles (SBMBs) in combination with ultrasound on ovarian cancer in vitro. Methods: SBMBs were prepared using mechanical vibration. The viability of A2780 cells was determined using the MTT assay. Flow cytometry was performed to detect cell apoptosis and the cell cycle. The expression of receptor tyrosine kinase (RTK)-associated downstream proteins was detected using multiplex assays and Western blots. Results: The present study designed and synthesized SBMBs. SBMBs in combination with ultrasound decreased A2780 cell viability in a dose- and time-dependent manner. The half maximal inhibitory concentration (IC50) showed that the cytotoxicity of the SBMBs was approximately 1.5 times greater than that of the SB in A2780 cells. SBMBs in combination with ultrasound resulted in significantly higher apoptosis efficiency compared to the SB group, and the SBMB population of cells was arrested in the G1/G0 phase. Further experiments demonstrated that SBMBs decreased the expression of signal transducer and activator of transcription 3 (STAT3), Ak strain transforming (AKT), and extracellular signal-regulated kinase (Erk) and had a greater effect than SB in A2780 cells. Inhibitors of AKT, Erk and STAT3 promoted the cytotoxicity of SBMBs. Conclusion: SBMBs in combination with ultrasound may enhance the cytotoxicity efficiency of SB via the promotion of apoptosis and cell cycle arrest in ovarian cancer cells and the inactivation of the STAT3, AKT and Erk signalling pathways.

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

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200227093216 ◽

2020 ◽

Vol 20 (13) ◽

pp. 1530-1537 ◽

Cited By ~ 4

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.

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Proteomic analysis of exosomes reveals an association between cell invasiveness and exosomal bioactivity on endothelial and mesenchymal cell migration in vitro

Clinical Science ◽

10.1042/cs20180425 ◽

2018 ◽

Vol 132 (18) ◽

pp. 2029-2044 ◽

Cited By ~ 11

Author(s):

Shayna Sharma ◽

Mona Alharbi ◽

Miharu Kobayashi ◽

Andrew Lai ◽

Dominic Guanzon ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Progression ◽

Buoyant Density ◽

Tumour Microenvironment ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Cell Of Origin ◽

Invasive Capacity

Ovarian cancer has resulted in over 140 000 deaths reported annually worldwide. This is often attributed to cellular changes in the microenvironment, including increased migration of mesenchymal stem cells (MSCs) and endothelial cells (ECs) to facilitate metastasis. Recently, the ability of exosomes to communicate signals between cells (and promote cancer progression) has been established. In the present study, we explored the effect of exosomes on cells present in the tumour microenvironment. Exosomes were isolated from ovarian cancer cells with different invasive capacity (high = SKOV-3 and low = OVCAR-3) by differential and buoyant density centrifugation and characterised using nanoparticle tracking analysis (NTA), Western blot, and EM. Exosome secretion was positively correlated with invasiveness of releasing cells. Proteomic analyses identified common and unique proteins between exosomes from SKOV-3 and OVCAR-3 with gene ontology analyses revealing that these exosomes are involved in the regulation of cell migration. Since the tumour microenvironment contains multiple cell types, including MSCs and ECs, we examined the effect of these exosomes on MSC and EC migration. Exosomes promoted MSC and EC migration in a time- and concentration-dependent manner. The effect of exosomes isolated from SKOV-3 on cell migration was significantly higher compared with exosomes from OVCAR-3. Thus, we suggest that exosomes from ovarian cancer cells contain a specific set of proteins that are representative of its cell of origin and the invasive capacity.

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Effects of naringin on reversing cisplatin resistance and the Wnt/β-catenin pathway in human ovarian cancer SKOV3/CDDP cells

Journal of International Medical Research ◽

10.1177/0300060519887869 ◽

2020 ◽

Vol 48 (10) ◽

pp. 030006051988786

Author(s):

Hong Zhu ◽

Xia Zou ◽

ShiXin Lin ◽

Xin Hu ◽

Jun Gao

Keyword(s):

Ovarian Cancer ◽

Cyclin D1 ◽

Western Blotting ◽

Cisplatin Resistance ◽

Malignant Tumors ◽

D1 Protein ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Prolonged Incubation

Objective Ovarian cancer is one of three malignant tumors of the female reproductive system. Our previous studies showed that the traditional Chinese medicine naringin significantly inhibited the proliferation of platinum-resistant ovarian cancer cells in vitro, and that the mechanism may be related to the NF-κB pathway. Methods The MTT assay was used to detect the sensitivity of SKOV3 and SKOV3/CDDP cells to cisplatin, the effect of different naringin concentrations on the proliferation of SKOV3/CDDP cells, and the reversal of cisplatin resistance in naringin-treated SKOV3/CDDP cells. Western blotting was used to detect β-catenin, c-Myc, and cyclin D1 protein levels in the different cell lines. Results MTT results showed that different concentrations of naringin inhibited the proliferation of SKOV3 and SKOV3/CDDP cells, and that the inhibition increased with increasing concentrations and prolonged incubation times. Western blotting revealed that compared with controls (SKOV3/CDDP-0), β-catenin, c-Myc and cyclin D1 proteins levels were significantly decreased in SKOV3/CDDP-C, SKOV3/CDDP-N 20, and SKOV3/CDDP-CN 20 cells, suggesting that naringin inhibited the proliferation of SKOV3/CDDP cells in a concentration and time dependent manner. Conclusions Non-cytotoxic naringin reduced the expression of β-catenin, c-Myc, and cyclin D1 in SKOV3/CDDP cells and partially reversed cisplatin resistance in SKOV3/CDDP CN 20 cells.

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Propranolol Suppresses Cobalt Chloride-Induced Hypoxic Proliferation in Human Umbilical Vein Endothelial Cells in vitro

Pharmacology ◽

10.1159/000494762 ◽

2018 ◽

Vol 103 (1-2) ◽

pp. 61-67 ◽

Cited By ~ 1

Author(s):

Li Wei ◽

Li Li ◽

Bin Zhang ◽

Lin Ma

Keyword(s):

Cell Cycle ◽

Endothelial Cells ◽

Cyclin D1 ◽

Cobalt Chloride ◽

Umbilical Vein ◽

Cell Counting ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells

Background/Aims: To investigate the effect of propranolol on cobalt chloride (CoCl2)-induced hypoxic proliferation in human umbilical vein endothelial cells (HUVECs). Methods: CoCl2 was administrated to HUVECs to mimic hypoxic proliferation in infantile hemangioma. The proliferation of HUVECs was detected by Cell Counting Kit-8. Effects of propranolol on apoptosis and expressions of cell cycle-related genes, CDK4 and cyclin D1, were detected by flow cytometry and RT-PCR respectively. The release of vascular endothelial growth factor (VEGF) and lactate dehydrogenase (LDH) was measured by enzyme-linked immunosorbent assay. Results: Propranolol significantly inhibited the CoCl2-induced hypoxic proliferation of HUVECs in a dose-dependent manner, and also induced apoptosis and suppressed the expression of CDK4 and cyclin D1. Propranolol also decreased the release of VEGF and LDH in the supernatant. Conclusions: Propranolol could inhibit CoCl2-induced hypoxic proliferation of HUVECs through inducing apoptosis and cell cycle arrest.

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222 ANTIFUNGAL AGENTS AS AGRICULTURAL PRODUCTS, FENHEXAMID, FLUDIOXONIL, AND CYPRODINIL, INDUCED THE EXPRESSION OF CYTOCHROME P450 FAMILY AND CELL CYCLE-RELATED GENES IN ESTROGEN RECEPTOR EXPRESSING BG-1 OVARIAN CANCER CELLS

Reproduction Fertility and Development ◽

10.1071/rdv27n1ab222 ◽

2015 ◽

Vol 27 (1) ◽

pp. 201

Author(s):

R.-E. Go ◽

K.-C. Choi

Keyword(s):

Ovarian Cancer ◽

Cell Viability ◽

Cyclin D1 ◽

Cancer Cells ◽

Antifungal Agents ◽

Negative Control ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Environmental Carcinogens ◽

Expression Levels

Fenhexamid, fludioxonil, and cyprodinil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. The induction of CYP gene expression including CYP1A1 and CYP1B1 is mediated by the transformation of polycyclic aromatic hydrocarbons (PAHs), and modulated by aryl hydrocarbon receptor (AhR). CYP1A1 is expressed in the liver, pancreas, thymus, uterus, and small intestine. CYP1B1 is abundant in the prostate, breast, and uterus. Expression levels of CYP1A1 and CYP1B1 indicate PAH-induced immunotoxicity, oxidative stress, and activation of environmental carcinogens. In this study, the ability of cell viability was examined as MTT assay by pesticides; fenhexamid, fludioxonil and cyprodinil. In addition, expression levels of mRNA and protein of AhR, CYP1A1, and Cyclin D1 were analysed by RT-PCR and Western blot analysis in BG-1 ovarian cancer cells with oestrogen receptors (ER). To evaluate the ability of cell viability, BG-1 cells were cultured with a negative control (0.1% DMSO), 17β-oestradiol (E2; 1 × 10–9 M), fenhexamid, fludioxonil or cyprodinil (10–5–10–8 M). To evaluate the expression levels of mRNA and protein, BG-1 cells were cultured with a negative control (0.1% DMSO), 17β-oestradiol (E2; 10–9 M) and these pesticides (10–5 M). As results, E2 as a positive control markedly increased BG-1 cell viability ~5 times compared to a negative control (P < 0.05). In addition, treatments with these pesticides increased BG-1 cell viability at the concentrations of 10–8 and 10–5 M about from 1.5 to 2 times, respectively (P < 0.05). When respective treatment co-treated with ICI 182 780, an ER antagonist, BG-1 cell viability was reversed to the level of a negative control. The mRNA expression of CYP1A1 was increased by E2, fenhexamid, and cyprodinil in a time-dependent manner but not by fludioxonil, while its level was reversed in the presence of ICI 182 780. In parallel with their transcriptional levels, protein levels of CYP1A1 and cyclin D1 were induced by E2 and these pesticides, while the level of AhR was not altered by E2 and these pesticides. Taken together, these results imply that the pesticides, fenhexamid, fludioxonil, and cyprodinil, may have disruptive effects on ER expressing cells or tissues by alteration of CYP1A1 and cyclin D1 via an ER-dependent pathway.

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G1cell cycle progression and the expression of G1cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells

AJP Cell Physiology ◽

10.1152/ajpcell.00422.2003 ◽

2004 ◽

Vol 287 (2) ◽

pp. C281-C291 ◽

Cited By ~ 200

Author(s):

Ning Gao ◽

Daniel C. Flynn ◽

Zhuo Zhang ◽

Xiao-Song Zhong ◽

Valerie Walker ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Kinase Inhibitor ◽

Ovarian Cancer Cells ◽

Cycle Progression ◽

Cycle Arrest ◽

Pi3k Activity

Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer cells. PI3K is involved in multiple cellular functions, including proliferation, differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study, we demonstrate that the inhibition of PI3K activity by LY-294002 inhibited ovarian cancer cell proliferation and induced G1cell cycle arrest. This effect was accompanied by the decreased expression of G1-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser780, Ser795, and Ser807/811. Expression of CDK6 and β-actin was not affected by LY-294002. Expression of the cyclin kinase inhibitor p16INK4awas induced by the PI3K inhibitor, whereas steady-state levels of p21CIP1/WAF1were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not extracellular regulated kinase 1/2. The G1cell cycle arrest induced by LY-294002 was restored by the expression of active forms of AKT and p70S6K1 in the cells. Our study shows that PI3K transmits a mitogenic signal through AKT and mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had similar inhibitory effects on G1cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G1progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.

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