Abstract
Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.
Highlights
Pancreatic cancer is the tenth most prominent type of malignant tumor in humans, with a low rate of early diagnosis, high malignancy, and a five-year-survival rate of only 6% [1]
The combined treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) showed a significant downregulating effect on the proliferating cell nuclear antigen (PCNA) protein level the single treatment at the same concentration did not have such an effect (Fig 1C). These results indicated that combined treatment with liraglutide and metformin was more effective than the single treatment in inhibiting the proliferation of the human pancreatic cancer cells
Meta-analysis showed that patients with diabetes mellitus who received metformin treatment had a 37% lower risk of developing pancreatic cancer and that metformin use was associated with better survival outcomes in patients with pancreatic cancer [17,18]
Summary
Pancreatic cancer is the tenth most prominent type of malignant tumor in humans, with a low rate of early diagnosis, high malignancy, and a five-year-survival rate of only 6% [1]. Based on several clinical studies and meta-analysis, it is well accepted that diabetes is one of the risk factors for pancreatic cancer [2]. Patients with diabetes show about a 2-fold risk of developing pancreatic ductal adenocarcinoma (PDAC) [2,3]. The tumor-derived influence on glucose metabolism can cause the dysfunction of pancreatic beta cells, elevation of blood glucose, and eventually development of diabetes [4].
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