Growth suppression of human pancreatic cells by a novel PKCβ inhibitor, enzastaurin

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14141-14141
Author(s):  
H. Cheng ◽  
J. G. Yan ◽  
Y. Jiang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Mtt Assay ◽  
Low Dose ◽  
Soft Agar ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Cells ◽  
Transforming Activity

14141 Background: Human pancreatic cancer is a devastating disease. Standard therapy, gemcitabine, is not able to alter the natural history of the disease. Targeting intracellular signaling molecules has proven to be a powerful approach in cancer therapy. Protein kinase C (PKC) family has been implicated in many human cancers including pancreatic cancer. Methods: In this pre-clinical study, we evaluated the effect of a novel small molecule inhibitor, enzastaurin, for PKCβ on human pancreatic cancer cells. We utilized MTT assay to assess cell proliferation and viability. To evaluate cell transforming activity, soft agar colony forming assay was used. Results: We showed that with addition of 20μM enzastaurin into the culture, the proliferative growth of two pancreatic cancer cell lines, Panc1 and L3.6p1, was significantly attenuated, as measured by the MTT assay. In addition, the combination of enzastaurin and a low dose of gemcitabine (25 nM) resulted in a synergistic cytotoxic effect in L3.6p1 cells. Further, the in vitro tumorogenicity assay demonstrated that the L3.6p1 cells treated with enzastaurin (20μM) formed much smaller colonies than the control parental cells in 0.4% soft-agar. Consistent with the in vitro cell proliferation results, the combination of enzastaurin and the low concentration of gemcitabine (25nM) further reduced the numbers and sizes of colonies in the soft-agar. Conclusions: Collectively, our data indicate that enzastaurin can effectively suppress the proliferation and in vitro transforming activity of the pancreatic cells, and more effectively when applied in combination with the low dose of gemcitabine. No significant financial relationships to disclose.

Growth inhibitory effect of ceramide-incorporated nanoliposomes in human pancreatic cancer cells

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14105-14105
Author(s):  
Y. Jiang ◽  
J. Kaiser ◽  
Y. Heakal ◽  
H. Cheng ◽  
T. Loughran ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Caspase 3 ◽  
Pancreatic Cancer Cell ◽  
Soft Agar ◽  
Human Pancreatic Cancer ◽  
Transforming Activity ◽  
C6 Ceramide ◽  
Colony Forming Assay

14105 Background: In cancer therapy, it is a challenging task to develop an optimal therapeutic regimen with an improved drug delivery vehicle and a cancer targeting strategy. Liposome-based drug delivery vehicles have been proven feasible and effective in clinical applications. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a lipid-derived second messenger that is proapoptotic to cancer cells, but not to normal cells. Methods: MTT assay was used to evaluate cell proliferation and viability. In vitro soft agar colony forming assay was utilized to assess the transforming activity of pancreatic cancer cell lines. For apoptosis, caspase 3/7 assay was applied. Results: We assessed the biological effect of C6-ceramide nanoliposomes (C6 liposome) in two human pancreatic cancer cell lines, L3.6p1 and Panc1 cells. We demonstrated in L3.6p1 cells as well as Panc1 cells that C6 liposomes, but not control liposomes, increased cytotoxicity, as measured by MTT assay. Moreover, the C6 liposome synergized with low dose gemcitabine, a first line pancreatic cancer neoplastic agent, to dramatically enhance apoptosis, as measured by caspase 3/7 activities. Further, in vitro transforming assays (soft agar colony forming assay) indicated that L3.6p1 cells treated with C6 liposome formed much smaller colonies than that of control cells, suggesting that the C6 liposome alone can inhibit the in vitro transforming ability of the L3.6p1 cells. Conclusions: Collectively, we have developed a novel nanotechnology-based liposomal drug delivery system for pancreatic tumors. Our data suggest that the C6 liposomal formulation is able to enhance the efficacy of gemcitabine to suppress the proliferation and in vitro transforming activity of pancreatic tumor cells. Acknowlegements: Penn State Research Foundation has licensed ceramide liposomes to Tracon Pharmaceutical, Inc. San Diego, CA. No significant financial relationships to disclose.

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.

scholarly journals Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 249
Author(s):  
Ruediger Goess ◽  
Ayse Ceren Mutgan ◽  
Umut Çalışan ◽  
Yusuf Ceyhun Erdoğan ◽  
Lei Ren ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Islet Cells ◽  
Human Pancreatic Cancer ◽  
Type I ◽  
Type Iv ◽  
Pancreatic Cancer Cells

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

Nordihydroguaiaretic acid inhibits growth and induces apoptosis in human pancreatic cancer cells in vitro and in vivo

2000 ◽  
Vol 118 (4) ◽  
pp. A540
Author(s):  
Thomas Seufferlein ◽  
Michael J. Seckl ◽  
Michael Beil ◽  
Hardi Luhrs ◽  
Roland M. Schmid ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Nordihydroguaiaretic Acid ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

2019 ◽  
Vol 19 (5) ◽  
pp. 417-427 ◽  
Author(s):  
Xiang Chen ◽  
Jilai Tian ◽  
Gloria H. Su ◽  
Jiayuh Lin
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Human Pancreatic Cancer ◽  
Multiple Cancer ◽  
Pancreatic Cancer Cells ◽  
Stat3 Phosphorylation

Background:Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance.Objective:We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer.Methods:The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay.Results:We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells.Conclusion:Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.

Identification and characterization of CCK-B/gastrin receptors in human pancreatic cancer cell lines

1994 ◽  
Vol 266 (1) ◽  
pp. R277-R283 ◽  
Author(s):  
J. P. Smith ◽  
G. Liu ◽  
V. Soundararajan ◽  
P. J. McLaughlin ◽  
I. S. Zagon
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Human Pancreatic Cancer Cell ◽  
Pancreatic Cancer Cells

The gastrointestinal peptide cholecystokinin (CCK) is known to stimulate growth of human pancreatic cancer in a receptor-mediated fashion. The purpose of this study was to characterize the receptor responsible for the trophic effects of CCK in cancer cells. With the use of homogenates of PANC-1 human pancreatic cancer cells grown in vitro, the binding characteristics and optimal conditions of radiolabeled selective CCK-receptor antagonists ([3H]L-365,260 and [3H]L-364,718) were examined. Specific and saturable binding was detected with [3H]L-365,260, and Scatchard analysis revealed that the data were consistent for a single site of binding with a binding affinity of 4.3 +/- 0.6 nM and a binding capacity (Bmax) of 283 +/- 68 fmol/mg protein in log phase cells. Binding was dependent on protein concentration, time, temperature, and pH and was sensitive to Na+, K+, Mg2+, and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In contrast to log phase cells, Bmax decreased by 80 and 92% in confluent and postconfluent cultures, respectively. Subcellular fractionation studies revealed that binding was in the membrane fraction. Competition experiments indicated that L-365,260 and gastrin were more effective at displacing the radiolabeled L-365,260 than CCK. No binding was detected with the CCK-A antagonist [3H]L-364,718. Assays performed with [3H]L-365,260 on five additional human pancreatic cancer cell lines in vitro and tumor tissue from xenografts in nude mice also revealed specific and saturable binding. These results provide the first identification of a CCK-B/gastrin receptor in human pancreatic cancer cells and tumors and explain the effects of CCK on the growth of this malignancy.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

scholarly journals Long Noncoding RNA TUG1/miR-29c Axis Affects Cell Proliferation, Invasion, and Migration in Human Pancreatic Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yebin Lu ◽  
Ling Tang ◽  
Zhipeng Zhang ◽  
Shengyu Li ◽  
Shuai Liang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Matrix Metalloproteinase ◽  
Human Pancreatic Cancer ◽  
Matrix Metalloproteinase 2 ◽  
Integrin Subunit ◽  
Normal Tissues

Given the low resection rate and chemoresistance of patients with pancreatic cancer (PC), their survival rates are typically poor. Long noncoding RNAs (lncRNAs) have recently been shown to play an important role in tumourigenesis and human cancer progression, including in PC. In this study, we aimed to investigate the role of taurine-upregulated gene 1 (TUG1) in PC. A quantitative polymerase chain reaction was used to analyse TUG1 expression in PC tissues and peritumoural normal tissues. TUG1 was overexpressed in PC tissues compared with that in peritumoural normal tissues, and the high expression of TUG1 was associated with the poor prognosis of patients with PC. Furthermore, TUG1 knockdown significantly inhibited the proliferation and invasion of PC cells both in vitro and in vivo, while overexpression TUG1 promoted tumour cell proliferation, migration, and invasion. TUG1 directly targeted miR-29c, a tumour suppressor in several cancers. TUG1 knockdown significantly increased the expression of miR-29c and subsequently induced the downregulation of integrin subunit beta 1 (ITGB1), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9). The downregulation of miR-29c abolished the TUG1 knockdown-mediated inhibition of tumour growth in vitro and in vivo, whereas the upregulation of miR-29c enhanced the effects of TUG1 knockdown on PC cells. In conclusion, we demonstrate for the first time the oncogenic role of TUG1 in PC. The downregulation of TUG1 significantly inhibited the growth and migratory ability of PC cells in vitro and in vivo by targeting miR-29c. Our study provides a novel potential diagnostic biomarker and therapeutic target for PC.

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