130P IL-2-armed oncolytic vaccinia virus exerts potent antitumor effects in human pancreatic cancer

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.

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Lister strain of vaccinia virus armed with endostatin–angiostatin fusion gene as a novel therapeutic agent for human pancreatic cancer

Gene Therapy ◽

10.1038/gt.2009.74 ◽

2009 ◽

Vol 16 (10) ◽

pp. 1223-1233 ◽

Cited By ~ 38

Author(s):

J R Tysome ◽

A Briat ◽

G Alusi ◽

F Cao ◽

D Gao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Vaccinia Virus ◽

Therapeutic Agent ◽

Fusion Gene ◽

Human Pancreatic Cancer ◽

Novel Therapeutic

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Differences in antitumor effects of various statins on human pancreatic cancer

International Journal of Cancer ◽

10.1002/ijc.23242 ◽

2007 ◽

Vol 122 (6) ◽

pp. 1214-1221 ◽

Cited By ~ 63

Author(s):

Helena Gbelcová ◽

Martin Leníček ◽

Jaroslav Zelenka ◽

Zdeněk Knejzlík ◽

Gabriela Dvořáková ◽

...

Keyword(s):

Pancreatic Cancer ◽

Human Pancreatic Cancer ◽

Antitumor Effects

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Curcumin Inhibits Tumor Growth and Angiogenesis in an Orthotopic Mouse Model of Human Pancreatic Cancer

BioMed Research International ◽

10.1155/2013/810423 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 34

Author(s):

Sabrina Bimonte ◽

Antonio Barbieri ◽

Giuseppe Palma ◽

Antonio Luciano ◽

Domenica Rea ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Cell Signalling ◽

Malignant Neoplasm ◽

Human Pancreatic Cancer ◽

Antitumor Effects ◽

Orthotopic Mouse Model ◽

Toxic Agents

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells.In vitrostudies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observedin vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway.

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Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21155190 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5190

Author(s):

Kaho Hirai ◽

Saiichiro Watanabe ◽

Nozomi Nishijima ◽

Kaoru Shibata ◽

Akane Hase ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Viability ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Human Pancreatic Cancer ◽

Choline Uptake ◽

Antitumor Effects ◽

Choline Transporter ◽

Pancreatic Cancer Cells ◽

Mouse Xenograft Model

Choline, an organic cation, is one of the biofactors that play an important role in the structure and the function of biological membranes, and it is essential for the synthesis of phospholipids. Choline positron emission tomography-computed tomography (PET/CT) provides useful information for the imaging diagnosis of cancers, and increased choline accumulation has been identified in a variety of tumors. However, the molecular mechanisms of choline uptake and choline transporters in pancreatic cancer have not been elucidated. Here, we examined molecular and functional analyses of choline transporters in human pancreatic-cancer cell line MIA PaCa-2 and the elucidation of the action mechanism behind the antitumor effect of novel choline-transporter-like protein 1 (CTL1) inhibitors, Amb4269951 and its derivative Amb4269675. CTL1 and CTL2 mRNAs were highly expressed in MIA PaCa-2 cells, and CTL1 and CTL2 proteins were localized in the plasma membrane and the intracellular compartments, respectively. Choline uptake was characterized by Na+-independence, a single-uptake mechanism, and inhibition by choline-uptake inhibitor HC-3, similar to the function of CTL1. These results suggest that the uptake of extracellular choline in MIA PaCa-2 cells is mediated by CTL1. Choline deficiency and HC-3 treatment inhibited cell viability and increased caspase 3/7 activity, suggesting that the inhibition of CTL1 function, which is responsible for choline transport, leads to apoptosis-induced cell death. Both Amb4269951 and Amb4269675 inhibited choline uptake and cell viability and increased caspase-3/7 activity. Ceramide, which is increased by inhibiting choline uptake, also inhibited cell survival and increased caspase-3/7 activity. Lastly, both Amb4269951 and Amb4269675 significantly inhibited tumor growth in a mouse-xenograft model without any adverse effects such as weight loss. CTL1 is a target molecule for the treatment of pancreatic cancer, and its inhibitors Amb4269951 and Amb4269675 are novel lead compounds.

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