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Antitumor Activity of Gemcitabine Can Be Potentiated in Pancreatic Cancer through Modulation of TLR4/NF-κB signaling by 6-Shogaol

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Abstract

Advanced pancreatic cancer still has a poor prognosis, even with the approval of several drugs, such as gemcitabine. Therefore, developing effective and safe antitumor agents is urgently needed. 6-Shogaol, a phenol extracted from ginger, has been linked to suppression of proliferation and survival of cancer with different mechanisms. In the present study, we investigated whether 6-shogaol could suppress pancreatic cancer progress and potentiate pancreatic cancer to gemcitabine treatment in vitro and in vivo. We found that 6-shogaol prevented the activation of toll like receptor 4 (TLR4)/NF-κB signaling. The modulation of NF-κB signaling by 6-shogaol was ascertained by electrophoretic mobility shift assay and western blot analysis. The suppression of NF-κB signaling and key cell survival regulators including COX-2, cyclinD1, survivin, cIAP-1, XIAP, Bcl-2, and MMP-9 brought the anti-proliferation effects in pancreatic cancer cells and sensitized them to gemcitabine treatment. Furthermore, in a pancreatic cancer xenograft model, we found a decreased proliferation index (Ki-67) and increased apoptosis by TUNEL staining in 6-shogaol treated tumors. It was also shown that 6-shogaol combined with gemcitabine treatment was more effective than drug alone, consistent with the downregulation of NF-κB activity along with its target genes COX-2, cyclinD1, survivin, cIAP-1, and XIAP. Overall, our results suggest that 6-shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-κB-mediated inflammatory pathways linked to tumorigenesis.

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Acknowledgments

This work was supported by the National Science Foundation of China (No. 81001618), the National Science &Technology Pillar Program during the Twelfth Five-year Plan Period (2012BAI29B07), and program for New Century Excellent Talents in University (NCET-12-0976).

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China

    Ling Zhou, Lianwen Qi, Lifeng Jiang, Ping Zhou, Jiang Ma, Xiaojun Xu & Ping Li

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  1. Ling Zhou
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  2. Lianwen Qi
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Correspondence to Xiaojun Xu or Ping Li.

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Ling Zhou and Lianwen Qi contributed equally to this work.

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Zhou, L., Qi, L., Jiang, L. et al. Antitumor Activity of Gemcitabine Can Be Potentiated in Pancreatic Cancer through Modulation of TLR4/NF-κB signaling by 6-Shogaol. AAPS J 16, 246–257 (2014). https://doi.org/10.1208/s12248-013-9558-3

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