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Article

Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma

  • Authors:
    • Keiichi Suzuki
    • Osamu Takeuchi
    • Yukio Suzuki
    • Yuko Kitagawa
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Kitasato Institute Hospital, Tokyo 108‑8642, Japan, Biomedical Laboratory, Kitasato Institute Hospital, Tokyo 108‑8642, Japan, Department of Pharmacy, Research and Education Center for Clinical Pharmacy, Division of Clinical Medicine, Kitasato University School of Pharmacy, Tokyo 108‑8641, Japan, Department of Surgery, Keio University School of Medicine, Tokyo 160‑8582, Japan
  • Pages: 764-772
    |
    Published online on: December 10, 2018
       https://doi.org/10.3892/ijo.2018.4662
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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 inhibited by incubation with MET, but not with GEM, and the expression of HIF‑1α under hypoxic conditions was significantly inhibited by MET treatment, but not by GEM treatment. The production of vascular endothelial growth factor was also suppressed by MET treatment, but not by GEM treatment, as determined by ELISA. Taken together, the data of this study demonstrate that the anti‑tumor activity of MET is mediated via the suppression of mTOR‑HIF‑1 signaling, reflecting a different underlying mechanism of action than that of GEM. These results may prove to be clinically significant and reveal the potential of MET as an effective therapeutic drug for PDAC.
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Copy and paste a formatted citation
Spandidos Publications style
Suzuki K, Takeuchi O, Suzuki Y and Kitagawa Y: Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma. Int J Oncol 54: 764-772, 2019.
APA
Suzuki, K., Takeuchi, O., Suzuki, Y., & Kitagawa, Y. (2019). Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma. International Journal of Oncology, 54, 764-772. https://doi.org/10.3892/ijo.2018.4662
MLA
Suzuki, K., Takeuchi, O., Suzuki, Y., Kitagawa, Y."Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma". International Journal of Oncology 54.2 (2019): 764-772.
Chicago
Suzuki, K., Takeuchi, O., Suzuki, Y., Kitagawa, Y."Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma". International Journal of Oncology 54, no. 2 (2019): 764-772. https://doi.org/10.3892/ijo.2018.4662
Copy and paste a formatted citation
x
Spandidos Publications style
Suzuki K, Takeuchi O, Suzuki Y and Kitagawa Y: Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma. Int J Oncol 54: 764-772, 2019.
APA
Suzuki, K., Takeuchi, O., Suzuki, Y., & Kitagawa, Y. (2019). Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma. International Journal of Oncology, 54, 764-772. https://doi.org/10.3892/ijo.2018.4662
MLA
Suzuki, K., Takeuchi, O., Suzuki, Y., Kitagawa, Y."Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma". International Journal of Oncology 54.2 (2019): 764-772.
Chicago
Suzuki, K., Takeuchi, O., Suzuki, Y., Kitagawa, Y."Mechanisms of metformin's anti‑tumor activity against gemcitabine‑resistant pancreatic adenocarcinoma". International Journal of Oncology 54, no. 2 (2019): 764-772. https://doi.org/10.3892/ijo.2018.4662
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