scholarly journals COXIBs and 2,5-dimethylcelecoxib counteract the hyperactivated Wnt/β-catenin pathway and COX-2/PGE2/EP4 signaling in glioblastoma cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Aleksandra Majchrzak-Celińska ◽  
Julia O. Misiorek ◽  
Nastassia Kruhlenia ◽  
Lukasz Przybyl ◽  
Robert Kleszcz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Methylation Status ◽  
Receptor Expression ◽  
Cell Cycle Distribution ◽  
Ep4 Receptor ◽  
Cox 2 ◽  
The Impact

Abstract Background Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/β-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/β-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. Methods Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of β-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. Results Wnt/β-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. Conclusions Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.

Anlotinib Inhibits Cell Proliferation, Migration and Invasion via Suppression of c-met Pathway and Activation of ERK1/2 Pathway in H446 Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Xiali Tang ◽  
Ying Zheng ◽  
Demin Jiao ◽  
Jun Chen ◽  
Xibang Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Cell Cycle Distribution ◽  
M Cell ◽  
Invasion And Migration ◽  
Cycle Arrest ◽  
And Migration

Background: Small Cell Lung Cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. The purpose of this study was to investigate the effect of anlotinib on SCLC and the potential molecular mechanisms. Methods: Cell viability was assessed by CCK-8 assay to determine the adequate concentration of anlotinib. Then, effects of anlotinib on cell apoptosis, cell cycle distribution, migration and invasion were analyzed by flow cytometry, PI staining, wound healing assay and transwell assay, respectively. The protein expression of c-met and ERK1/2 pathways in H446 cells were assessed by western blot analysis. Result: In this study, we found that anlotinib significantly reduced the cell viability of H446 cells, induced G2/M cell cycle arrest and decreased invasion and migration of H446 cells. Futhermore, we also found that anlotinib could suppress c-met signal transduction and activate the ERK1/2 pathway in H446 cells. More importantly, c-met was involved in the effects of anlotinib on migration and invasion in H446 cells. Conclusion: Taken together, our results demonstrated that anlotinib was a potential anticancer agent that inhibited cell proliferation, migration and invasion via suppression of the c-met pathway and activation of the ERK1/2 pathway in H446 cells.

scholarly journals Impact of the APE1 Redox Function Inhibitor E3330 in Non-Small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 550 ◽  
Author(s):  
Rita Manguinhas ◽  
Ana S. Fernandes ◽  
João G. Costa ◽  
Nuno Saraiva ◽  
Sérgio P. Camões ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Viability ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
The Impact

Elevated expression levels of the apurinic/apyrimidinic endonuclease 1 (APE1) have been correlated with the more aggressive phenotypes and poor prognosis of non-small cell lung cancer (NSCLC). This study aimed to assess the impact of the inhibition of the redox function of APE1 with E3330 either alone or in combination with cisplatin in NSCLC cells. For this purpose, complementary endpoints focusing on cell viability, apoptosis, cell cycle distribution, and migration/invasion were studied. Cisplatin decreased the viability of H1975 cells in a time- and concentration-dependent manner, with IC50 values of 9.6 µM for crystal violet assay and 15.9 µM for 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. E3330 was clearly cytotoxic for concentrations above 30 µM. The co-incubation of E3330 and cisplatin significantly decreased cell viability compared to cisplatin alone. Regarding cell cycle distribution, cisplatin led to an increase in sub-G1, whereas the co-treatment with E3330 did not change this profile, which was then confirmed in terms of % apoptotic cells. In addition, the combination of E3330 and cisplatin at low concentrations decreased collective and chemotactic migration, and also chemoinvasion, by reducing these capabilities up to 20%. Overall, these results point to E3330 as a promising compound to boost cisplatin therapy that warrants further investigation in NSCLC.

High Glucose Affects the Cytotoxic Potential of Rapamycin, Metformin and Hydrogen Peroxide in Cultured Human Mesenchymal Stem Cells

2019 ◽  
Vol 19 (9) ◽  
pp. 688-698 ◽  
Author(s):  
Azam Roohi ◽  
Mahin Nikougoftar ◽  
Hamed Montazeri ◽  
Shadisadat Navabi ◽  
Fazel Shokri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hydrogen Peroxide ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Viability ◽  
High Glucose ◽  
Cell Cycle Distribution ◽  
Efficient Treatment ◽  
Chronic Hyperglycemia ◽  
Placental Mesenchymal Stem Cells

Background: Oxidative stress and chronic hyperglycemia are two major side effects of type 2 diabetes affecting all cell types including mesenchymal stem cells (MSCs). As a cell therapy choice, understanding the behavior of MSCs will provide crucial information for efficient treatment. Methods: Placental mesenchymal stem cells were treated with various concentrations of glucose, metformin, rapamycin, and hydrogen peroxide to monitor their viability and cell cycle distribution. Cellular viability was examined via the MTT assay. Cell cycle distribution was studied by propidium iodide staining and apoptosis was determined using Annexin Vpropidium iodide staining and flow cytometry. Involvement of potential signaling pathways was evaluated by Western blotting for activation of Akt, P70S6K, and AMPK. Results: The results indicated that high glucose augmented cell viability and reduced metformin toxic potential. However, the hydrogen peroxide and rapamycin toxicities were exacerbated. Conclusion: Our findings suggest that high glucose concentration has a major effect on placental mesenchymal stem cell viability in the presence of rapamycin, metformin and hydrogen peroxide in culture.

VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Aikebaier Maimaiti ◽  
Amier Aili ◽  
Hureshitanmu Kuerban ◽  
Xuejun Li
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Gallic Acid ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Dependent Manner ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis ◽  
The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

scholarly journals S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines

2014 ◽  
Vol 24 (4) ◽  
pp. 629-634 ◽  
Author(s):  
Qiaoying Zhu ◽  
Jianming Hu ◽  
Huijuan Meng ◽  
Yufei Shen ◽  
Jinhua Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Significant Inhibition ◽  
S Phase ◽  
Phase Cell ◽  
Cell Cycle Distribution ◽  
Human Ovarian Cancer ◽  
Skov3 Cell ◽  
Skov3 Cells

ObjectiveAplasia Ras homolog member I (ARHI) is associated with human ovarian cancer (HOC) growth and proliferation; however, the mechanisms are unclear. The purpose of this study was to investigateARHIeffects in HOC SKOV3 cells.MethodsWe transfected SKOV3 cells with PIRES2-EGFP-ARHI and measured growth inhibition rates, cell cycle distribution, apoptosis rates, and expression of P-STAT3 (phosphorylated signal transduction and activators of transcription 3) and P-ERK (phosphorylated extracellular signal regulated protein kinase).ResultsOur data showed significant inhibition of growth, significantly increased S-phase arrest and apoptosis rates, and reduction of P-STAT3 and P-ERK1/2 expression levels.ConclusionsWe propose the mechanism may involveARHI-induced phosphorylation of ERK1/2 and STAT3 protein kinases, thereby blocking proliferation signaling pathways, to induce HOC SKOV3 apoptosis.

scholarly journals Cytotoxic Potential of the Coelomic Fluid Extracted from the Sea Cucumber Holothuria tubulosa against Triple-Negative MDA-MB231 Breast Cancer Cells

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 76 ◽  
Author(s):  
Claudio Luparello ◽  
Debora Ragona ◽  
Dalia Maria Lucia Asaro ◽  
Valentina Lazzara ◽  
Federica Affranchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Sea Cucumber ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Water Soluble ◽  
Coelomic Fluid ◽  
Cell Cycle Distribution ◽  
Widespread Species ◽  
Tnbc Cell

Growing evidence has demonstrated that the extracts of different holothurian species exert beneficial effects on human health. Triple negative breast cancers (TNBC) are highly malignant tumors that present a poor prognosis due to the lack of effective targeted therapies. In the attempt to identify novel compounds that might counteract TNBC cell growth, we studied the effect of the exposure of the TNBC cell line MDA-MB231 to total and filtered aqueous extracts of the coelomic fluid obtained from the sea cucumber Holoturia tubulosa, a widespread species in the Mediterranean Sea. In particular, we examined cell viability and proliferative behaviour, cell cycle distribution, apoptosis, autophagy, and mitochondrial metabolic/cell redox state. The results obtained indicate that both total and fractionated extracts are potent inhibitors of TNBC cell viability and growth, acting through both an impairment of cell cycle progression and mitochondrial transmembrane potential and a stimulation of cellular autophagy, as demonstrated by the increase of the acidic vesicular organelles and of the intracellular protein markers beclin-1, and total LC3 and LC3-II upon early exposure to the preparations. Identification of the water-soluble bioactive component(s) present in the extract merit further investigation aiming to develop novel prevention and/or treatment agents efficacious against highly metastatic breast carcinomas.

C/EBPβ Isoforms Regulate Proliferation and Differentiation of Regenerating Hematopoietic Stem/Progenitor Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3713-3713
Author(s):  
Atsushi Sato ◽  
Asumi Yokota ◽  
Yoshihiro Hayashi ◽  
Naoka Kamio ◽  
Satoshi Sagai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Flow Cytometric Analysis ◽  
Myeloid Cells ◽  
Stress Conditions ◽  
Hematopoietic Stem ◽  
N Terminus ◽  
Factor C ◽  
The Impact

Under stress or regenerative conditions, HSCs rapidly enter into cell cycle and are reprogrammed toward myeloid-biased hematopoiesis to meet the increasing demand of myeloid cells. We have previously shown that the transcription factor C/EBPβ plays critical roles at the level of HSPCs under stress conditions (Nat Immunol 2006, J Immunol 2012, Leukemia 2013 and Blood Adv 2019). However, underlying molecular mechanisms of action remain largely unknown. In this study, we have investigated the detailed function of C/EBPβ in regulation of HSPCs. We first evaluated the impact of C/EBPβ on the cell cycle status of LT-HSCs. To exclude the cell-extrinsic contribution of C/EBPβ, CD45.2+ BM cells from WT or Cebpb-/- mice were transplanted into lethally irradiated CD45.1+ WT mice, and these "BM-replaced" recipients were subjected to the following experiments. At steady state, the cell cycle statuses and the numbers of HSPCs did not significantly differ between the recipients of WT cells and those of Cebpb-/- cells. Immediately after 5-FU treatment, WT LT-HSCs entered the cell cycle, as revealed by the decreased percentage of cells in G0 phase and the increased percentage of cells in S/G2M phase. All these parameters of cell cycle acceleration were observed prior to the nadir of LT-HSCs induced by 5-FU and were significantly attenuated in Cebpb-/- LT-HSCs. Next, we assessed the numbers of LT-HSCs, KSL cells, and KL cells after 5-FU treatment. Following the nadir, the recovery of LT-HSCs preceded that of KSL and KL cells, suggesting the differentiation of LT-HSCs to KSL and KL cells. In the recipients of Cebpb-/- cells, the recovery of KSL and KL cells was delayed significantly. Collectively, cell cycle acceleration and subsequent differentiation of LT-HSCs under stress conditions were impaired in the absence of Cebpb. The Cebpb is a single exon gene, and three isoforms, namely, LAP*, LAP and LIP which lacks N-terminus, are translated from its unique mRNA. Due to their structural difference, they should have distinct functions. Here, we focused on expression and functions of these isoforms in regenerating HSPCs. To monitor expression of these isoforms in small numbers of HSCs, we devised a novel intracellular double staining method for flow cytometric analysis using two distinct anti-C/EBPβ antibodies. An antibody against the C-terminus of C/EBPβ recognized all three isoforms, while an antibody against the N-terminus of C/EBPβ only recognized LAP* and LAP. Thus, simultaneous staining with both antibodies should enable us to distinguish cells that dominantly expressed LIP (C-term+ N-term-) from those that expressed all three isoforms (C-term+ N-term+). Using this method, we monitored the expression patterns of these isoforms in LT-HSCs after 5-FU treatment. LT-HSCs initially became C-term single positive in response to 5-FU and subsequently changed to C- and N-term double positive, suggesting that LIP was upregulated prior to LAP/LAP* under stress conditions. These results suggest that phase-specific upregulation of LIP and LAP/LAP* is strongly associated with phase-specific functions of C/EBPβ in cell cycle activation and differentiation, respectively. Indeed, when EML cells, a mouse HSC line, were retrovirally transduced with LIP, the transduced cells were more proliferative and actively cycling than those transduced with the control vector, whereas proliferation and cell cycle were markedly suppressed in LAP*- and LAP-expressing EML cells. LIP-expressing cells remained undifferentiated, while LAP*- and LAP-expressing cells rapidly differentiated into CD11b+ myeloid cells and eventually stopped proliferating. In summary, our findings clearly suggest that sequential upregulation of C/EBPβ isoforms is critical for the regulation of HSCs under stress conditions. LIP amplifies the "reservoir" of HSPCs by accelerating the proliferation of HSCs during the early phase of regeneration, while LAP*/LAP induce their myeloid differentiation at a later phase. These findings should facilitate our understanding of the pathophysiology of infection, inflammation, and regenerating hematopoiesis in response to myeloablative chemotherapies or hematopoietic stem cell transplantation, all of which increase the hematopoietic demands. Disclosures Hirai: Kyowa Kirin: Research Funding.

Resveratrol induces cell cycle arrest and apoptosis in epithelioid malignant pleural mesothelioma cells

2017 ◽  
Vol 43 (2) ◽  
pp. 197-204
Author(s):  
Saime Batirel ◽  
Ergul Mutlu Altundag ◽  
Selina Toplayici ◽  
Ceyda Corek ◽  
Hasan Fevzi Batirel
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Malignant Pleural Mesothelioma ◽  
Cell Cycle Distribution ◽  
Pleural Mesothelioma ◽  
Dependent Manner ◽  
P53 Expression ◽  
Cycle Arrest

Abstract Background: Resveratrol is a natural anti-carcinogenic polyphenol. Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis. In this study, we investigated the effects of resveratrol on epithelioid MPM. Material and methods: Human epithelioid MPM cell line (NCI-H2452) was exposed to resveratrol (5–200 μM) for 24 or 48 h. Cell viability was assessed by WST-1 assay. Flow cytometry analyses were performed to evaluate the effects of resveratrol on cell cycle distribution and apoptosis. Western blot analysis was used to determine protein expression levels of antioxidant enzymes, cyclin D1 and p53. Reactive oxygen species (ROS) were measured using H2DCFDA. Results: Resveratrol reduced cell viability of the cells in a concentration and time dependent manner. After treatment, the cells accumulated in G0/G1 phase and the percentage of cells in G2/M phase was reduced. Resveratrol decreased cyclin D1 and increased p53 expression in cell lysates. Treated cells exhibited increased apoptotic activity. ROS were elevated with resveratrol treatment, but there was no change in the expression of superoxide dismutase (SOD)-1, SOD-2 and glutathione peroxidase. Conclusion: Our results revealed that resveratrol exhibits anti-cell viability effect on epithelioid MPM cells by inducing cell cycle arrest and apoptosis. Resveratrol may become a potential therapeutic agent for epithelioid MPM.

p38 MAP kinase mediates mechanically induced COX-2 and PG EP4 receptor expression in podocytes: implications for the actin cytoskeleton

2004 ◽  
Vol 286 (4) ◽  
pp. F693-F701 ◽  
Author(s):  
Louis C. Martineau ◽  
Lyne I. McVeigh ◽  
Bernard J. Jasmin ◽  
Chris R. J. Kennedy
Keyword(s):  
Actin Cytoskeleton ◽  
Map Kinase ◽  
Mechanical Stress ◽  
P38 Map Kinase ◽  
Receptor Expression ◽  
Prostaglandin E ◽  
Glomerular Permeability ◽  
Ep4 Receptor ◽  
Filtration Barrier ◽  
Cox 2

A dynamic cytoskeleton allows podocytes to withstand significant mechanical stress on elevation of intraglomerular capillary pressure (Pgc). However, vasoactive hormones, such as prostaglandin E2 (PGE2), may challenge the integrity of the actin cytoskeleton, alter podocyte morphology, and compromise glomerular permeability. PGE2 synthesis correlates with the onset of proteinuria and increased Pgc following reduced nephron mass. We investigated the interplay among mechanical stress, cyclooxygenase (COX), E-prostanoid (EP) receptor expression, and the actin cytoskeleton, using an in vitro model of cell stretch. Immortalized mouse podocytes grown on flexible silicone membranes were cyclically stretched (5% elongation, 0.5 Hz) for 2 h. EP4 and COX-2 mRNA increased three- and sevenfold above nonstretched controls, whereas EP1 and COX-1 levels were unchanged. Six hours of stretch resulted in a threefold increase in PGE2-stimulated cAMP accumulation, a measure of EP4 receptor function, and an increase in COX-2 protein. The stretch-induced effects on COX-2/EP4 expression and EP4-induced cAMP production were attributable to p38 MAP kinase, as blockade of this pathway, but not of ERK or JNK, abrogated the response. These stretch-induced changes in expression were transcriptionally dependent as they were actinomycin D sensitive. Finally, we investigated the influence of enhanced EP4 signaling on the actin cytoskeleton. Addition of PGE2 resulted in actin filament depolymerization observable only in stretched cells. Our results indicate that key components of the eicosanoid pathway are upregulated by mechanically stimulated p38 MAP kinase in podocytes. Enhanced EP4 receptor signaling may undermine podocyte cytoskeletal dynamics and thereby compromise filtration barrier function under conditions of increased Pgc.

scholarly journals Evaluation of anticancer and antimicrobial activities of the Polygonum maritimum ethanol extract

2018 ◽  
Vol 70 (4) ◽  
pp. 665-673 ◽  
Author(s):  
Marina Jovanovic ◽  
Tatjana Srdic-Rajic ◽  
Emilija Svircev ◽  
Nebojsa Jasnic ◽  
Biljana Nikolic ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Herbal Remedy ◽  
Antimicrobial Properties ◽  
Epigallocatechin Gallate ◽  
Ethanol Extract ◽  
Antimicrobial Activities ◽  
Cell Cycle Distribution ◽  
M Cell ◽  
Ic50 Values

Polygonum maritimum is a traditional herbal remedy that produces abundant flavonoid secondary metabolites. The ethanol extract of P. maritimum aerial parts (POM) was chemically characterized and tested for antimicrobial properties and cytotoxicity. Results of LC-MS/MS analysis showed high contents of gallic acid, epigallocatechin gallate and catechin, and significant amounts of quercetin-3-O-galactoside and quercetin-3-O-glucoside. Evaluation of the antifungal properties revealed that POM induced notable growth inhibition of Alternaria alternata (34.3%), Penicillium spp. (30.6%), Fusarium semitectum (20.2%) and Aspergillus spp. (19.6%). Evaluation of cytotoxicity against human hepatoma HepG2 cells included monitoring the effects of both POM alone and its combination with cytostatic doxorubicin (Dox). Cell viability, apoptosis and cell cycle distribution and the expression of antioxidant enzymes (superoxide-dismutases SOD1 and SOD2 and catalase) were determined. A dose-dependent decrease in cell viability was detected, but a remarkably stronger effect was obtained when POM and Dox were applied in combination as compared to individual treatments. IC50 values were determined to be 393 ?g/mL (POM) and 2.24 ?g/mL (Dox) in combination, but 1153 ?g/mL (POM) and 12.56 ?g/mL (Dox) in a single treatment. The value of the Loewe index, determined for IC50, was notably lower than 1 (LI=0.51), clearly indicating synergism of POM and Dox. Additionally, POM and POM +Dox induced early/late apoptosis and G2/M cell cycle arrest. Furthermore, POM increased, while Dox decreased the expression levels of SODs and catalase. The obtained results encourage further examination of the potential use of POM in modern phytotherapy.

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