Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma
Abstract
Metformin (MET) is the first‑line treatment for type 2 diabetes mellitus. Several epidemiological studies have suggested the potential anti‑cancer effects of MET, including its activity against pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM) has become the standard chemotherapy for PDAC; however, acquired resistance to GEM is a major challenge. In this study, we evaluated the anti‑tumor effects of MET against GEM‑resistant PDAC in a mouse xenograft model. GEM‑resistant BxG30 PDAC cells were implanted into BALB/c nude mice. The mice were divided into 4 groups (control, GEM, MET, and combined treatment with GEM + MET) and treated with the drugs for 4 weeks. Compared with the control mice, the final tumor volumes were significantly decreased in the mice treated with GEM + MET. Treatment to control volume ratios (T/C%) were calculated as 80.2% (GEM), 54.0% (MET) and 47.2% (GEM + MET). The anti‑tumor activity of GEM alone against BxG30 tumor xenografts was limited. MET treatment alone exerted satisfactory anti‑tumor effects; however, the optimal T/C% was achieved by treatment with GEM + MET, indicating that this combined treatment regimen potently inhibited the growth of GEM‑resistant PDAC. The expression of hypoxia‑inducible factor 1α (HIF‑1α) and the phosphorylation of ribosomal protein S6 (S6), an important downstream effector of the mammalian target of rapamycin (mTOR) signaling pathway, were also assessed by western blot analysis. The phosphorylation of S6 was…
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