An engineered anti-CA19-9 cys-diabody for PET imaging of pancreas cancer and targeting of polymerized liposomal nanoparticles.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 198-198
Author(s):  
M. D. Girgis ◽  
K. McCabe ◽  
T. Olafsen ◽  
F. Bergara ◽  
V. Kenanova ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Mouse Xenograft Model ◽  
Parental Antibody ◽  
G Ratio

198 Background: Antibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments, such as the cys-diabody demonstrate similar antigen affinity compared to the parental antibody but have a shorter serum half-life (4hrs) and possess the ability to be conjugated to nanoparticles. Our goal was to engineer an anti-CA19-9 cys-diabody fragment in hopes of imaging and targeting pancreatic cancer. Methods: The anti-CA19-9 cys-diabody was created by cloning the variable region of the parental antibody, engineering a C-terminus cysteine, expressing in NS0 cells followed by protein purification utilizing HPLC. Maleimide chemistry was used to conjugate the cys-diabody to PLNs through the engineered cysteine residues. Immunofluorescence and flow cytometry were used to evaluate targeting of cys-diabody and diabody conjugated PLNs to human pancreatic cancer cell lines. The cys-diabody was evaluated in a mouse xenograft model harboring CA19-9 positive (BxPC3) and negative (MiaPaca) tumors. The cys-diabody was radiolabeled with a positron emitter (I-124) and microPET/CT were performed after tail vein injection. Percent of injected dose per gram (%ID/g) of radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images. Results: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 cys- diabody. Tumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor:blood (%ID/g) ratio of 3.3 and positive:negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by immunofluorescence showing specific targeting of PLN-cys- diabody conjugate to human pancreatic cancer cells in vitro. Conclusions: Our results show that the anti-CA19.9 cys- diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the PLN-cys-diabody conjugate targets human pancreatic cancer cells with the potential to deliver targeted treatment. Further studies evaluating the in vivo ability of the PLN-cys-diabody conjugate to target pancreatic cancer need to be performed. No significant financial relationships to disclose.

The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells

2018 ◽  
Vol 40 (6) ◽  
pp. 805-818 ◽  
Author(s):  
Sharleen V Menezes ◽  
Leyla Fouani ◽  
Michael L H Huang ◽  
Bekesho Geleta ◽  
Sanaz Maleki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Metastasis Suppressor ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
E Cadherin

AbstractThe metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.

scholarly journals Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2331 ◽  
Author(s):  
JebaMercy Gnanasekaran ◽  
Adi Binder Gallimidi ◽  
Elias Saba ◽  
Karthikeyan Pandi ◽  
Luba Eli Berchoer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Porphyromonas Gingivalis ◽  
Xenograft Model ◽  
Oral Bacteria ◽  
Oral Microbiome ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Increased Risk

Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo. To the best of our knowledge, this study is the first to demonstrate the direct effect of exposure to P. gingivalis on the tumorigenic behavior of pancreatic cancer cell lines. Our findings shed light on potential mechanisms underlying the pancreatic cancer–periodontitis link.

ERO1α promotes hypoxic tumour progression and is associated with poor prognosis in pancreatic cancer

2019 ◽  
Author(s):  
Nikhil Gupta ◽  
Jung Eun Park ◽  
Wilford Tse ◽  
Jee Keem Low ◽  
Oi Lian Kon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumour Progression ◽  
Xenograft Model ◽  
Early Stage Disease ◽  
Hypoxia Stress ◽  
Pancreatic Cancer Cells ◽  
Proteomic Approach ◽  
Mouse Xenograft Model

AbstractPancreatic cancer is a leading cause of mortality worldwide due to difficulty detecting early-stage disease and our poor understanding of the mediators that drive the progression of hypoxic solid tumours. We, therefore, used a heavy isotope ‘pulse/trace’ proteomic approach to determine how hypoxia alters pancreatic tumour expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistant (ABCB6), immune suppression (NFIL3,WDR4), angiogenesis (ANGPT4, ERO1α, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1α was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1α substantially reduced growth rates and colony formation in pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1α-deficient tumour cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1α is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.

scholarly journals Light Stability, Pro-Apoptotic and Genotoxic Properties of Silver (I) Complexes of Metronidazole and 4-Hydroxymethylpyridine against Pancreatic Cancer Cells In Vitro

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3848
Author(s):  
Dominik Żyro ◽  
Agnieszka Śliwińska ◽  
Izabela Szymczak-Pajor ◽  
Małgorzata Stręk ◽  
Justyn Ochocki
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Silver Nitrate ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

Antimicrobial properties of silver (I) ion and its complexes are well recognized. However, recent studies suggest that both silver (I) ion and its complexes possess anticancer activity associated with oxidative stress-induced apoptosis of various cancer cells. In this study, we aimed to investigate whether silver nitrate and its complexes with metronidazole and 4-hydroxymethylpyridine exert anticancer action against human pancreatic cancer cell lines (PANC-1 and 1.2B4). In the study, we compared decomposition speed for silver complexes under the influence of daylight and UV-A (ultraviolet-A) rays. We employed the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide) assay to evaluate the cytotoxicity and the alkaline comet assay to determine genotoxicity of silver nitrate and its complexes. Flow cytometry and the Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of human pancreatic cancer cells. We found a dose dependent decrease of both pancreatic cancer cell line viability after exposure to silver nitrate and its complexes. The flow cytometry analysis confirmed that cell death occurred mainly via apoptosis. We also documented that the studied compounds induced DNA damage. Metronidazole and 4-hydroxymethylpyridine alone did not significantly affect viability and level of DNA damage of pancreatic cancer cell lines. Complex compounds showed better stability than AgNO3, which decomposed slower than when exposed to light. UV-A significantly influences the speed of silver salt decomposition reaction. To conclude, obtained data demonstrated that silver nitrate and its complexes exerted anticancer action against human pancreatic cancer cells.

scholarly journals A natural food sweetener with anti-pancreatic cancer properties

Oncogenesis ◽  
2016 ◽  
Vol 5 (4) ◽  
pp. e217-e217 ◽  
Author(s):  
C Liu ◽  
L-H Dai ◽  
D-Q Dou ◽  
L-Q Ma ◽  
Y-X Sun
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Angiogenic Factor ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Natural Food ◽  
Vascular Density ◽  
Pancreatic Cancer Cells ◽  
Mouse Xenograft Model

Abstract Mogroside V is a triterpenoid isolated from the traditional Chinese medical plant Siraitia grosvenorii. Mogroside V has a high degree of sweetness and a low calorific content. Herein, we found that mogroside V possesses tumor growth inhibitory activity in in vitro and in vivo models of pancreatic cancer by promoting apoptosis and cell cycle arrest of pancreatic cancer cells (PANC-1 cells), which may in part be mediated through regulating the STAT3 signaling pathway. These results were confirmed in vivo in a mouse xenograft model of pancreatic cancer. In xenograft tumors, Ki-67 and PCNA, the most commonly used markers of tumor cell proliferation, were downregulated after intravenous administration of mogroside V. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that mogroside V treatment promoted apoptosis of pancreatic cancer cells in the xenograft tumors. Furthermore, we found that mogroside V treatment significantly reduced the expression of CD31-labeled blood vessels and of the pro-angiogenic factor vascular endothelial growth factor in the xenografts, indicating that mogroside V might limit the growth of pancreatic tumors by inhibiting angiogenesis and reducing vascular density. These results therefore demonstrate that the natural, sweet-tasting compound mogroside V can inhibit proliferation and survival of pancreatic cancer cells via targeting multiple biological targets.

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

2010 ◽  
Vol 999 (999) ◽  
pp. 1-11
Author(s):  
P. Ulivi ◽  
C. Arienti ◽  
W. Zoli ◽  
M. Scarsella ◽  
S. Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Efficacy ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2017
Author(s):  
Lital Sharvit ◽  
Rinat Bar-Shalom ◽  
Naiel Azzam ◽  
Yaniv Yechiel ◽  
Solomon Wasser ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Culture Liquid ◽  
Human Pancreatic Cancer ◽  
P53 Signaling ◽  
Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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