Abstract
The influence of Glucagon-like peptide-1 (GLP-1) and Exendin-4 on development of intrahepatic cholangiocarcinoma (ICC) is evaluated in the study. In vitro tests, including acute toxicity test, cell colony formation assays, cells proliferation and apoptosis, transwell assay, were performed. An ICC in situ tumor animal model was established. Then, animals were randomly divided into four groups (n = 6): control, Exendin-4 treatment, oxaliplatin treatment and Exendin-4-oxaliplatin treatment. Animals in the Exendin-4 treatment and Exendin-4-oxaliplatin treatment groups received a subcutaneous injection of Exendin-4 (100 μg/kg/day) for 1 week, and then received oxaliplatin (10 mg/kg/week) by tail vein injection. Animals in the control group received PBS. Immunohistochemistry tests were used for PCNA, Ki67, Caspase 3 expression in tumor tissue. Results show that that, after incubation of human cholangiocarcinoma cell lines, HuCCTI and GLP-1, or HuCCTI and Exendin-4, colony formation number was sharply decreased. However, GLP-1, HuCCTI or Exendin-4 did not affect the colony of normal cells. Combination treatment with oxaliplatin and Exendin-4 can significantly inhibit tumor cells’ proliferation and promote apoptosis. The combined effect is stronger than that of oxaliplatin or Exendin-4. Combination treatment with oxaliplatin and Exendin4 can significantly decrease Ki67 and PCNA proteins’ expression in subcutaneous tumors of nude mice. The inhibitory effect of Combination treatment with oxaliplatin and Exendin4 is clearly stronger than that of oxaliplatin. In addition, Combination treatment with oxaliplatin and Exendin4 can significantly increase Caspase3 protein positive expression. In short, these results show that combination treatment with oxaliplatin and Exendin4 can inhibit tumor cells’ proliferation, and promote apoptosis.
Highlights
Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted by intestinal L cells, is a promising therapeutic agent in the treatment of diabetes
Based on our previous studies [11] about the analysis of clinical data of intrahepatic cholangiocarcinoma and immunohistochemical staining, we find that positive expression of GLP-1 receptors (GLP-1Rs) is very high in intrahepatic cholangiocarcinoma tissue, indicating that
We found that effect of Exendin4 on intrahepatic cholangiocarcinoma cell line
Summary
Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted by intestinal L cells, is a promising therapeutic agent in the treatment of diabetes. A major target for GLP-1 actions is the pancreatic β-cell. One of the main physiological roles of this endocrine hormone is to enhance insulin secretion in a glucose-dependent manner [1,2,3]. The physiological relevance and pharmacology of GLP-1 have been researched extensively, with a major focus on its incretin actions, and its application in the treatment of type-2 diabetes. The administration of GLP-1 is not effective as a treatment for diabetes, because the protein is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). GLP-1 receptor agonists that are resistant to DPP-4 and DPP-4 inhibitors are currently being used for the treatment of type 2 diabetes [4]
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