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Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

ABSTRACT: BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. CONCLUSION/SIGNIFICANCE: In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion.

SUBMITTER: Mayorek N

PROVIDER: S-EPMC2939880 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

Mayorek Nina N Naftali-Shani Nili N Grunewald Myriam M

PloS one 20100915 9

<h4>Background</h4>Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically.<h4>Methodology/principal findings</h4>We found that dicl ...[more]

PMID: 20856806

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Project description:BackgroundGrb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear.MethodsThe expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis.ResultsUp-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels.ConclusionsThe results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.

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Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

Publications

Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

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