Role of Oxidative and Nitro-Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5-year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today’s oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro-oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC-1). Previously, we have found that AgNPs induced PANC-1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro-oxidative stress in this cytotoxic effect of AgNPs against PANC-1 cells. We determined AgNP-induced increase of ROS level in PANC-1 cells and pancreatic noncancer cell (hTERT-HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC-1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX-4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro-oxidative stress and mitochondrial disruption are implicated in AgNPs-mediated death in human pancreatic ductal adenocarcinoma cells.

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BRM270 Inhibits the Proliferation of CD44 Positive Pancreatic Ductal Adenocarcinoma Cells via Downregulation of Sonic Hedgehog Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/8620469 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Do Luong Huynh ◽

Hyebin Koh ◽

Nisansala Chandimali ◽

Jiao Jiao Zhang ◽

Nameun Kim ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Ductal Adenocarcinoma ◽

Cell Phenotype ◽

Sonic Hedgehog Signaling ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Adenocarcinoma Cells

Pancreatic cancer has a poor survival rate as compared to other types of cancer. Surface marker CD44 plays important role in epithelial-mesenchymal transition and cancer stem cell phenotype. Therefore, targeting CD44 positive pancreatic cancer cells might enhance therapies effectiveness. Our previous studies indicated the antitumorigenesis effect of BRM270 in osteosarcoma, lung cancer, and glioblastoma; however there is no evidence on BRM270 impacts on pancreatic cancer growth. In this study, we investigated the effect of BRM270 on the isolated CD44 positive pancreatic ductal adenocarcinoma cells (CD44+PDAC). Results showed that CD44 positive cells undergo apoptosis induced by BRM270. Moreover, BRM270 also inhibits stemness and metastasis traits in CD44+PDAC via Sonic hedgehog signaling pathway and SALL4 expression.In vivostudy indicated that tumor growth derived from CD44+PDAC was suppressed as daily uptake by BRM270 5 mg/kg. These data suggest the alternative approach in antipancreatic tumorigenesis via herbal plants extract and selectively targeting CD44+PDAC cells in tumor.

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CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽

10.3390/cancers12092546 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2546

Author(s):

Leonie Hartl ◽

JanWillem Duitman ◽

Hella L. Aberson ◽

Kan Chen ◽

Frederike Dijk ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Suppressor ◽

Pancreatic Ductal Adenocarcinoma ◽

Binding Protein ◽

Ductal Adenocarcinoma ◽

Ductal Cells ◽

Enhancer Binding Protein ◽

Adenocarcinoma Cells ◽

Ccaat Enhancer Binding Protein

CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer. We determined C/EBPδ expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBPδ is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBPδ correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBPδ re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBPδ in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBPδ activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.

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Neurotensin is a Versatile Modulator of In Vitro Human Pancreatic Ductal Adenocarcinoma Cell (PDAC) Migration

Analytical Cellular Pathology ◽

10.1155/2007/701789 ◽

2007 ◽

Vol 29 (4) ◽

pp. 315-326

Author(s):

Tatjana Mijatovic ◽

Philippe Gailly ◽

Véronique Mathieu ◽

Nancy De Nève ◽

Paul Yeaton ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Rho Gtpases ◽

Small Gtpase ◽

Ductal Adenocarcinoma ◽

Computer Assisted ◽

Altered Expression ◽

Adenocarcinoma Cells ◽

Small Rho Gtpases

Background: While the neurotensin (NT) roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs) were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.

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The Anti-Tumor Activity of Afatinib in Pancreatic Ductal Adenocarcinoma Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200508090515 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1447-1458

Author(s):

Zhenyu Ye ◽

Yecheng Li ◽

Jiaming Xie ◽

Zhenyu Feng ◽

Xiaodong Yang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Underlying Mechanism ◽

Resistant Cell ◽

Resistant Cell Line ◽

Ductal Adenocarcinoma ◽

Adenocarcinoma Cells ◽

The Social ◽

New Perspective

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer and leading causes of pancreatic cancer death because of most PDAC patients with advanced unresectable disease at that time, which is remarkably resistant to all forms of chemotherapy and radiotherapy. Objective: PDAC increases the social and patient's family burden. However, the PDAC pathogenesis is not identified. We are trying to uncover the underlying mechanism in the future. Methods: In our research, the drug-resistant cell line was successfully induced in the vitro by progressive concentrations of Afatinib, which we named it as BxPC3-AR. Results: It has been observed that the effect of autophagy was on the resistance of BxPC3-AR to Afatinib. Conclusion: It has been confirmed that autophagy plays a certain role in BxPC3-AR resistance to Afatinib. Our findings provide a new perspective on the role of autophagy in pancreatic ductal adenocarcinoma.

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Computer-morphometric description of pancreatic ductal adenocarcinoma cells

Clinical anatomy and operative surgery ◽

10.24061/1727-0847.13.4.2014.4 ◽

2014 ◽

Vol 13 (4) ◽

pp. 19-22

Author(s):

A. V. Yevsieiev

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Adenocarcinoma Cells

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Effect of Shuangdan Mingmu capsule, a Chinese herbal formula, on oxidative stress-induced apoptosis of pericytes through PARP/GAPDH pathway

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03238-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fujiao Nie ◽

Jiazhao Yan ◽

Yanjun Ling ◽

Zhengrong Liu ◽

Chaojun Fu ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Oxidative Damage ◽

Damage Model ◽

B Cell Lymphoma ◽

Cell Counting ◽

Network Pharmacology ◽

Diabetic Patients ◽

Induced Apoptosis

Abstract Background Diabetic retinopathy (DR) has become a worldwide concern because of the rising prevalence rate of diabetes mellitus (DM). Despite much energy has been committed to DR research, it remains a difficulty for diabetic patients all over the world. Since apoptosis of retinal microvascular pericytes (RMPs) is the early characteristic of DR, this study aimed to reveal the mechanism of Shuangdan Mingmu (SDMM) capsule, a Chinese patent medicine, on oxidative stress-induced apoptosis of pericytes implicated with poly (ADP-ribose) polymerase (PARP) / glyceraldehyde 3-phosphate dehydrogenase (GAPDH) pathway. Methods Network pharmacology approach was performed to predict biofunction of components of SDMM capsule dissolved in plasma on DR. Both PARP1 and GAPDH were found involved in the hub network of protein-protein interaction (PPI) of potential targets and were found to take part in many bioprocesses, including responding to the regulation of reactive oxygen species (ROS) metabolic process, apoptotic signaling pathway, and response to oxygen levels through enrichment analysis. Therefore, in vitro research was carried out to validate the prediction. Human RMPs cultured with media containing 0.5 mM hydrogen oxide (H2O2) for 4 h was performed as an oxidative-damage model. Different concentrations of SDMM capsule, PARP1 inhibitor, PARP1 activation, and GAPDH inhibitor were used to intervene the oxidative-damage model with N-Acetyl-L-cysteine (NAC) as a contrast. Flow cytometry was performed to determine the apoptosis rate of cells and the expression of ROS. Cell counting kit 8 (CCK8) was used to determine the activity of pericytes. Moreover, nitric oxide (NO) concentration of cells supernatant and expression of endothelial nitric oxide synthase (eNOS), superoxide dismutase (SOD), B cell lymphoma 2 (BCL2), vascular endothelial growth factor (VEGF), endothelin 1 (ET1), PARP1, and GAPDH were tested through RT-qPCR, western blot (WB), or immunocytochemistry (ICC). Results Overproduction of ROS, high apoptotic rate, and attenuated activity of pericytes were observed after cells were incubated with media containing 0.5 mM H2O2. Moreover, downregulation of SOD, NO, BCL2, and GAPDH, and upregulation of VEGFA, ET1, and PARP1 were discovered after cells were exposed to 0.5 mM H2O2 in this study, which could be improved by PARP1 inhibitor and SDMM capsule in a dose-dependent way, whereas worsened by PARP1 activation and GAPDH inhibitor. Conclusions SDMM capsule may attenuate oxidative stress-induced apoptosis of pericytes through downregulating PARP expression and upregulating GAPDH expression.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00138.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. G524-G536 ◽

Cited By ~ 12

Author(s):

Sandrina Maertin ◽

Jason M. Elperin ◽

Ethan Lotshaw ◽

Matthias Sendler ◽

Steven D. Speakman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Oxidative Phosphorylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Environmental Stresses ◽

Ductal Adenocarcinoma ◽

Cell Adaptation ◽

Autophagy Inhibition ◽

Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

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