U0126 inhibits pancreatic cancer progression via the KRAS signaling pathway in a zebrafish xenotransplantation model.

Abstract

Pancreatic cancer is one of the most aggressive human cancers, and the pharmaceutical outcomes for its treatment remain disappointing. Proper animal models will provide an efficient platform for investigating novel drugs, and the zebrafish has become one of the most promising and comprehensive model animal in cancer research. In the present study, we used a novel xenograft model in zebrafish by transplanting human pancreatic cancer cells to study the progression and metastasis of pancreatic cancer cells and to assay the pharmacological effects of new drug U0126 in vivo. We first established a primary xenograft model of pancreatic cancer by injecting human pancreatic cancer cells into both live larval and adult zebrafish, and then investigated the behaviors of CM-DiI‑labeled human pancreatic cancer cells. Subsequently, we tested the potential of this model for drug screening by evaluating a known small-molecule inhibitor, U0126, which targets the KRAS signaling pathway. Cells with KRAS mutations exhibited significant proliferative and migratory behaviors and invaded the zebrafish vasculature system. In contrast, the proliferation and migration of Mia PaCa-2 cells in zebrafish larvae were substantially repressed following U0126 treatment. These results suggest that zebrafish xenotransplantation can be used as a simple and efficient tool to screen and identify new anti-pancreatic cancer compounds.

• Authors: Meng Guo, Huanhuan Wei, Jingying Hu, Shaoyang Sun, Jiang Long, Xu Wang
• Journal: Oncology reports (Oncol Rep) Vol. 34 Issue 2 Pg. 699-706 (Aug 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 26035715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Butadienes
• Nitriles
• U 0126
• Zebrafish Proteins
• Kras protein, zebrafish
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Butadienes (administration & dosage, pharmacology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Nitriles (administration & dosage, pharmacology)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• Zebrafish (embryology)
• Zebrafish Proteins (genetics, metabolism)