scholarly journals Development of Parvifloron D-loaded Smart Nanoparticles to Target Pancreatic Cancer

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 216 ◽  
Author(s):  
Ana Santos-Rebelo ◽  
Catarina Garcia ◽  
Carla Eleutério ◽  
Ana Bastos ◽  
Sílvia Castro Coelho ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Targeted Delivery ◽  
Water Soluble ◽  
Pancreatic Cell ◽  
Pharmaceutical Dosage Form ◽  
Alternative Approach ◽  
Water Soluble Compound ◽  
Efficient Alternative ◽  
Method Yield

Pancreatic cancer is the eighth leading cause of cancer death worldwide. For this reason, the development of more effective therapies is a major concern for the scientific community. Accordingly, plants belonging to Plectranthus genus and their isolated compounds, such as Parvifloron D, were found to have cytotoxic and antiproliferative activities. However, Parvifloron D is a very low water-soluble compound. Thus, nanotechnology can be a promising delivery system to enhance drug solubility and targeted delivery. The extraction of Parvifloron D from P. ecklonii was optimized through an acetone ultrasound-assisted method and isolated by Flash-Dry Column Chromatography. Then, its antiproliferative effect was selectivity evaluated against different tumor cell lines (IC50 of 0.15 ± 0.05 μM, 11.9 ± 0.7 μM, 21.6 ± 0.5, 34.3 ± 4.1 μM, 35.1 ± 2.2 μM and 32.1 ± 4.3 μM for BxPC3, PANC-1, Ins1-E, MCF-7, HaCat and Caco-2, respectively). To obtain an optimized stable Parvifloron D pharmaceutical dosage form, albumin nanoparticles were produced through a desolvation method (yield of encapsulation of 91.2%) and characterized in terms of size (165 nm; PI 0.11), zeta potential (−7.88 mV) and morphology. In conclusion, Parvifloron D can be efficiently obtained from P. ecklonii and it has shown selective cytotoxicity to pancreatic cell lines. Parvifloron D nanoencapsulation can be considered as a possible efficient alternative approach in the treatment of pancreatic cancer.

scholarly journals Non-toxic low-cost heavy liquid separation in the Geological Survey of Greenland

1989 ◽  
Vol 145 ◽  
pp. 11-13
Author(s):  
P Schiøler
Keyword(s):  
Health Risk ◽  
Low Cost ◽  
Water Soluble ◽  
Heavy Liquid ◽  
Organic Liquids ◽  
Federal Republic Of Germany ◽  
Water Soluble Compound ◽  
Efficient Alternative ◽  
Sodium Polytungstate ◽  
Heavy Liquids

Density separation of mineral and sediment grains into fractions using heavy liquids traditionally employs organic compounds such as bromoform (density 2.89) and tetrabromoethane (density 2.96) which are known to be toxic even at very low concentrations (Van Haaften, 1969) and possibly carcinogenic. In addition, the separated grains are washed with organic solvents such as acetone which may be highly inflammable, and are also a health risk. In recent years, a new water soluble compound, sodium polytungstate (SPT), 3Na2WO4.9WO3.H2O, has become available as a medium for heavy liquid separations, offering an alternative to the heavy organic liquids. Hs use has been discussed by several workers (e.g. Plewinsky & Kamp, 1984; Krukowski, 1988) in a variety of geological settings. The present note summarises experience in GGU's palaeontological laboratory gained from working with SPT for a full year as a replacement for tetrabromoethane and bromoform in the separation of phosphatic microfossils from samples principally of Lower - Middle Cambrian age. Apart from improving the work environment by replacing high health-risk chernicals with water soluble products without known detrimental effects, SPT has proved to be both an economical and potentially efficient alternative to the organic heavy liquids. SPT is patented, and only available from Sometu, Falkenried 4, D 1000 Berlin 33, Federal Republic of Germany.

scholarly journals Establishment and Characterization of Immortalized Miniature Pig Pancreatic Cell Lines Expressing Oncogenic K-RasG12D

2020 ◽  
Vol 21 (22) ◽  
pp. 8820
Author(s):  
Hae-Jun Yang ◽  
Bong-Seok Song ◽  
Bo-Woong Sim ◽  
Yena Jung ◽  
Unbin Chae ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tumor Biology ◽  
Human Pancreatic Cancer ◽  
Miniature Pig ◽  
Pancreatic Cell ◽  
Treatment And Prevention ◽  
Acinar To Ductal Metaplasia

In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences from humans. Therefore, large animals may be more useful for the investigation of pancreatic cancer. Pigs have recently emerged as a new model of pancreatic cancer due to their similarities to humans, but no pig pancreatic cancer cell lines have been established for use in drug screening or analysis of tumor biology. Here, we established and characterized an immortalized miniature pig pancreatic cell line derived from primary pancreatic cells and pancreatic cancer-like cells expressing K-rasG12D regulated by the human PTF1A promoter. Using this immortalized cell line, we analyzed the gene expression and phenotypes associated with cancer cell characteristics. Notably, we found that acinar-to-ductal transition was caused by K-rasG12D in the cell line constructed from acinar cells. This may constitute a good research model for the analysis of acinar-to-ductal metaplasia in human pancreatic cancer.

Evaluation of a nonbiologic nanoparticle form of paclitaxel in metastatic pancreatic cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15076-e15076 ◽  
Author(s):  
Kouros Motamed ◽  
Larn Hwang ◽  
Chao Hsiao ◽  
Vuong N. Trieu
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Cell Lines ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
In Vitro Toxicity ◽  
Pancreatic Cell ◽  
Anti Tumor Activity

e15076 Background: The (nab-Pac)/Gemcitabine (Gem) combination has recently been shown to impart a significant survival advantage over Gem alone in patients with metastatic pancreatic cancer. The goal of this study was to define a non-biologic, nanoparticle paclitaxel (NBN-Pac) which has a similar toxicity profile and utilizes the same albumin-mediated transport mechanism. Herein, we report in vitro, preclinical and phase I clinical results for this NBN-Pac in metastatic pancreatic cancer. Methods: In vitro drug cytotoxicity was measured as mean IC50 values following a 72-h exposure in four pancreatic cell lines (MIA Paca-2 and Capan-1 and multi-drug resistant cell lines PANC-1 and ASPC-1). In vivo anti-tumor activities were assessed in xenografted MIA PaCa-2 and PANC-1 models in nude mice treated with three i.v. doses of NBN-Pac (20, 50 mg/kg) and Taxol (20 mg/kg) on days 0, 3, and 6 (q3dx3), and twelve i.v. doses of Gem (140 mg/kg) on every 3 days (q3dx12). A phase I clinical trial (N=18) was conducted to determine the MTD and the recommended phase II dose of the combination therapy with NBN-Pac (220-300 mg/m2, q3w) and Gem (1250 mg/m2) as primary endpoints in first line treatment of subjects with advanced pancreatic cancer. Reduction in the plasma levels of CA19-9 was measured as a PD biomarker. Results: The mean IC50 value of NBN-Pac in four pancreatic cell lines was approximately 30-fold lower than that of Gem. NBN-Pac formulation (50 mg/kg) produced superior anti-tumor activity in the two xenograft models tested over Taxol and Gem at clinically equivalent doses. Our phase I trial established the MTD of this NBN-Pac formulation as 300mg/m2. Moreover, 5 out of 16 subjects (31.3%) were CR or PR with 95% exact confidence interval of (11.0%, 58.7%). The median PFS time was 5.6 month (95% C.I = 2.9). The median OS time could not be estimated as the survival rate did not fall below 50%. Other safety variables revealed no significant abnormality that may have affected the result of the study. Conclusions: NBN-Paclitaxel formulation has superior anti-tumor activity vs. Taxol and Gem in in vitro toxicity assays, preclinical models of pancreatic cancer, as well in a phase I clinical study in patients with advanced pancreatic cancer.

The role of Notch3 signaling pathway in pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21049-21049 ◽  
Author(s):  
T. Dang ◽  
k. Vo ◽  
K. Washington ◽  
J. Berlin
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreas Cancer ◽  
Human Cancer ◽  
Pancreatic Cancer Cell Line ◽  
Pancreatic Tissue ◽  
Tissue Array ◽  
Pancreatic Cell

21049 Background: Given the extremely poor prognosis of patients diagnosed with pancreatic cancer, identifying new targets for therapeutic intervention is crucial in improving clinical outcome. Existing data support a role for Notch3 pathway in human cancer, pancreas cancer in specific and in normal pancreas development. Method: We developed a pancreatic tissue array. An antibody targeting the extracellular domain of Notch3 was used to evaluate expression levels, grading from 0 to 4+ to determine the prevalence of Notch3 in pancreatic cancer. Notch3 expression was used to correlate with clinical data (IRB approved). Using small interfering RNA (siRNA) we tested the downstream effects of Notch3 in pancreatic cancer cell line BxP3 in vitro. Furthermore, to study pharmacologic inhibition of Notch3 processing and activation we exposed Panc-1, HPAF II and BxP3 pancreas cancer cell lines to γ-secretase inhibitors (previously demonstrated to block upstream of Notch3 thereby inhibiting Notch3). Results: Strong staining (+2 or greater) for Notch3 was seen in 50 of 72 (69%) resected specimens. No correlation with survival or tumor grade was seen. Using siRNA, we demonstrated that inhibiting Notch3 downregulated the antiapoptotic protein Bcl-xL but not Bcl-2. When γ-secretase inhibitors (GSI and L-685,458) were used, the previously mentioned pancreatic cell lines demonstrated reduction in proliferation rates. Conclusion: Notch3 overexpression is common in pancreas cancer. While Notch 3 expression does not clearly correlate with survival, our in vitro data suggest that Notch3 affects apoptotic pathways and may represent a potential target for intervention in patients with pancreatic cancer. No significant financial relationships to disclose.

Evaluation of ON 01910.Na, a novel modulator of polo-like kinase 1 (Plk1) pathway, and development of a cyclin-B1-based predictive assay in pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3569-3569
Author(s):  
A. Jimeno ◽  
A. Chan ◽  
X. Zhang ◽  
J. Wheelhouse ◽  
A. Solomon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Ex Vivo ◽  
Cyclin B1 ◽  
Preclinical Model ◽  
Significant Activity ◽  
In Vivo Models ◽  
Pancreatic Cell ◽  
Ex Vivo Assay

3569 Background: Plk1 is a key mitotic regulator of the transition through the G2/M checkpoint in the cell cycle. This work aimed to evaluate the activity of ON 01910.Na, a Plk1 pathway modulator, in in vitro and in vivo models of pancreatic cancer (PaCa) and to discover biomarkers predictive of efficacy. Methods: ON 01910.Na was tested in 12 PaCa cell lines. Studies assessing Plk1 related markers were conducted to identify biomarkers. For validation a live collection of PaCa xenografts from fresh tumor samples obtained at the time of surgical resection was used (PancXenoBank). The ex vivo assay was based on fine-needle aspirate (FNA) biopsies. Results: ON 01910.Na showed equal activity to gemcitabine against PaCa cell lines. The activity of ON 01910.Na correlated with suppression of two downstream mediators of PLK1, CDC25C and cyclin B1 (by mRNA and protein). ON 01910.Na was tested in xenografts from representative pancreatic cell lines. The selected markers were evaluated in an ex vivo assay, using intra-tumor pharmacokinetics to select the dose of the assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Knockdown of cyclin B1 by siRNA had no effect per se or in the response of the resistant MiaPaca2 to either of the drugs. We next used the ex vivo assay to profile ten patient-derived cases from the PancXenoBank. Two cases were catalogued as potential responders. From each of these ten cases, a group of mice bearing at least 20 tumors received vehicle or ON 01910.Na for 28 days. There was a correlation between the ex vivo cyclin B1 assay and the sensitivity to the tested agent, as the 2 cases prospectively identified as sensitive met pre-specified criteria for response. Of the 8 tumors predicted to be resistant, only one was sensitive. In IHC testing cases showing ex vivo cyclin B1 down-regulation had also decreases in cyclin B1 protein, and there was a correlation between activity and IHC changes in cyclin B1. Conclusions: ON 01910.Na demonstrated significant activity in a preclinical model of PaCa. A rationally designed ex vivo cyclin B1-based assay not only identified cases sensitive to ON 01910.Na, but also replicated the pharmacodynamic events occurring after in vivo exposure. No significant financial relationships to disclose.

scholarly journals Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 350
Author(s):  
Benedikt Feuerecker ◽  
Philipp Biechl ◽  
Christian Veltkamp ◽  
Dieter Saur ◽  
Wolfgang Eisenreich
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acids ◽  
Cancer Cells ◽  
Treatment Response ◽  
Cell Lines ◽  
Metabolic Response ◽  
Gas Chromatography Mass Spectrometry ◽  
Glycolytic Flux ◽  
Pancreatic Cell ◽  
Pancreatic Cancer Cells

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a 13C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-13C6]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography–mass spectrometry (GC/MS). 13C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-13C6]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer.

scholarly journals Water Soluble Iron-Based Coordination Trimers as Synergistic Adjuvants for Pancreatic Cancer

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 66
Author(s):  
Marco Cordani ◽  
Esther Resines-Urien ◽  
Arturo Gamonal ◽  
Paula Milán-Rois ◽  
Lionel Salmon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Pancreatic Cancer Cell ◽  
Aqueous Media ◽  
Coordination Complexes ◽  
Water Soluble ◽  
Therapeutic Approaches ◽  
Iron Based ◽  
High Concentrations ◽  
First Time

Pancreatic cancer is a usually fatal disease that needs innovative therapeutic approaches since the current treatments are poorly effective. In this study, based on cell lines, triazole-based coordination trimers made with soluble Fe(II) in an aqueous media were explored for the first time as adjuvant agents for the treatment of this condition. These coordination complexes were effective at relatively high concentrations and led to an increase in reactive oxygen species (ROS) in two pancreatic cancer cell lines, PANC-1 and BXPC-3, and this effect was accompanied by a significant reduction in cell viability in the presence of gemcitabine (GEM). Importantly, the tested compounds enhanced the effect of GEM, an approved drug for pancreatic cancer, through apoptosis induction and downregulation of the mTOR pathway. Although further evaluation in animal-based models of pancreatic cancer is needed, these results open novel avenues for exploring these iron-based materials in biomedicine in general and in pancreatic cancer treatment.

scholarly journals Inclusion of cancer-associated fibroblasts in drug screening assays to evaluate pancreatic cancer resistance to therapeutic drugs

2021 ◽  
Author(s):  
Sarah Brumskill ◽  
Lawrence N. Barrera ◽  
Peter Calcraft ◽  
Caroline Phillips ◽  
Eithne Costello
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
3D Models ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Cancer Resistance ◽  
Pancreatic Cell ◽  
Chemotherapy Drugs

AbstractPancreatic ductal adenocarcinoma (PDAC) is characterised by a pro-inflammatory stroma and multi-faceted microenvironment that promotes and maintains tumorigenesis. However, the models used to test new and emerging therapies for PDAC have not increased in complexity to keep pace with our understanding of the human disease. Promising therapies that pass pre-clinical testing often fail in pancreatic cancer clinical trials. The objective of this study was to investigate whether changes in the drug-dosing regimen or the addition of cancer-associated fibroblasts (CAFs) to current existing models can impact the efficacy of chemotherapy drugs used in the clinic. Here, we reveal that gemcitabine and paclitaxel markedly reduce the viability of pancreatic cell lines, but not CAFs, when cultured in 2D. Following the use of an in vitro drug pulsing experiment, PDAC cell lines showed sensitivity to gemcitabine and paclitaxel. However, CAFs were less sensitive to pulsing with gemcitabine compared to their response to paclitaxel. We also identify that a 3D co-culture model of MIA PaCa-2 or PANC-1 with CAFs showed an increased chemoresistance to gemcitabine when compared to standard 2D mono-cultures a difference to paclitaxel which showed no measurable difference between the 2D and 3D models, suggesting a complex interaction between the drug in study and the cell type used. Changes to standard 2D mono-culture-based assays and implementation of 3D co-culture assays lend complexity to established models and could provide tools for identifying therapies that will match clinically the success observed with in vitro models, thereby aiding in the discovery of novel therapies.

Preclinical study of cytotoxicity and predictive markers of response to dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 with or without paclitaxel or nab-paclitaxel as a new therapeutic strategy in pancreatic cancer cell lines.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15007-e15007
Author(s):  
Arturo Loaiza-Bonilla ◽  
Muaiad Kittaneh ◽  
Victor Daniel Guardiola Amado ◽  
Krisztina Kovacs ◽  
Jaime R. Merchan
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Dependent Manner ◽  
Wild Type ◽  
Pancreatic Cell ◽  
Dual Inhibition ◽  
Dose Dependent

e15007 Background: Targeting the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3K-AKT-mTOR) pathway could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies. NVP-BEZ235 is an oral, targeted anticancer agent which exerts its potential activity through PI3K/mTOR dual inhibition. The paradoxical feedback activation of the PI3K/Akt pathway may compromise the efficacy of TORC1 inhibitors and provide the rationale for generating dual inhibitors in human pancreatic cancer. Methods: Kras mutant and wild-type human pancreatic cell lines were treated in vitro with BEZ235 and its combination with nab-paclitaxel. Antiproliferative effect per WST-1 assay was measured. Western blot analysis of S235/S236P-RPS6 and Akt (S473P-Akt, T308P-Akt) after exposure to BEZ235 was also performed. The potential synergistic and time-dependent effect at different concentrations of experimental agents was measured at different intervals. Results: BEZ235 reduced S473P-Akt, T308P-Akt and S235/S236P-RPS6 levels in a dose-dependent manner. Nab-paclitaxel at higher concentration exerts significant antiproliferative effects in a time-dependent fashion in pancreatic cell lines irrespective of Kras mutation status. BEZ235 in combination with nab-paclitaxel showed significant synergistic effect in a time and dose-dependent manner compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type Kras (BxPC-3) but not in cell lines with mutant Kras (MIA PaCa-2 and PANC-1), the latter leading to a paradoxical increase in proliferation in comparison with controls, suggesting an escape pathway. Conclusions: These results provide the preclinical rationale for studies examining the synthetic lethality and escape pathways of PI3K/mTOR dual inhibition in particular subtypes of pancreatic cancer cell lines. Kras may be studied as a potential predictive biomarker of response to these agents and their combination with standard chemotherapy.

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