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Article Open Access

Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer

  • Authors:
    • Sheng Chen
    • Ye Wang
    • Wen‑Long Zhang
    • Mao‑Sheng Dong
    • Jian‑Hua Zhang
  • View Affiliations / Copyright

    Affiliations: Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China, Department of Pathology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
    Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1461-1470
    |
    Published online on: February 8, 2017
       https://doi.org/10.3892/mmr.2017.6182
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Abstract

Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc‑1 and ASPC‑1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine‑resistant cells (GR‑HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR‑HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR‑HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR‑HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine‑induced EMT through the TWIST1/Slug pathway in the GR‑HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma‑associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug‑hENT1/RRM1 signaling and resensitized GR‑HPCCs to gemcitabine. Finally, sclareolide resensitized GR‑HPCCs to gemcitabine through inducing apoptosis; in vivo, the co‑administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine‑resistant pancreatic cancer, which resensitizes GR‑HPCCs to gemcitabine through mediating NICD and Gli1.
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Copy and paste a formatted citation
Spandidos Publications style
Chen S, Wang Y, Zhang WL, Dong MS and Zhang JH: Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer. Mol Med Rep 15: 1461-1470, 2017.
APA
Chen, S., Wang, Y., Zhang, W., Dong, M., & Zhang, J. (2017). Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer. Molecular Medicine Reports, 15, 1461-1470. https://doi.org/10.3892/mmr.2017.6182
MLA
Chen, S., Wang, Y., Zhang, W., Dong, M., Zhang, J."Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer". Molecular Medicine Reports 15.4 (2017): 1461-1470.
Chicago
Chen, S., Wang, Y., Zhang, W., Dong, M., Zhang, J."Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer". Molecular Medicine Reports 15, no. 4 (2017): 1461-1470. https://doi.org/10.3892/mmr.2017.6182
Copy and paste a formatted citation
x
Spandidos Publications style
Chen S, Wang Y, Zhang WL, Dong MS and Zhang JH: Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer. Mol Med Rep 15: 1461-1470, 2017.
APA
Chen, S., Wang, Y., Zhang, W., Dong, M., & Zhang, J. (2017). Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer. Molecular Medicine Reports, 15, 1461-1470. https://doi.org/10.3892/mmr.2017.6182
MLA
Chen, S., Wang, Y., Zhang, W., Dong, M., Zhang, J."Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer". Molecular Medicine Reports 15.4 (2017): 1461-1470.
Chicago
Chen, S., Wang, Y., Zhang, W., Dong, M., Zhang, J."Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer". Molecular Medicine Reports 15, no. 4 (2017): 1461-1470. https://doi.org/10.3892/mmr.2017.6182
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