Abstract
Purpose
Pancreatic cancer is an aggressive malignancy, which generally develops resistance to chemotherapy. Agents that are safe and can sensitize cancer to chemotherapy are urgently needed. Escin, a natural mixture of triterpene saponins isolated from Aesculus wilsonii Rehd, has been demonstrated to possess anti-cancer activity both in vitro and in vivo. The anti-cancer activity of escin could be, in part, due to the inactivation of nuclear factor-κB (NF-κB). In contrast, chemotherapy including gemcitabine could activate NF-κB and lead to chemoresistance. Here, for the first time, we investigated whether escin, via the inactivation of NF-κB, would potentiate the antitumor activity of gemcitabine in pancreatic cancer.
Methods
Cell viability and proliferation, apoptosis, NF-κB activity and the expression of NF-κB-linked genes were all examined in vitro. The antitumor effect of escin with or without gemcitabine in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice.
Results
Escin not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of gemcitabine in both BxPC-3 and PANC-1 cell lines in vitro, but also dramatically enhanced its suppressive effect on tumor growth in nude mice. The mechanism is at least partially due to the inhibition of NF-κB activity and consequent inhibition of c-Myc, COX-2, Cyclin D1, Survivin, Bcl-2 and Bcl-xL, and the activation of caspase-3.
Conclusion
These data suggest that escin, via inactivation of NF-κB, could potentiate the efficacy of gemcitabine in combating pancreatic cancer, which could be a novel and potentially important therapeutic approach for the treatment for pancreatic cancer.
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Acknowledgments
This work was supported in part by grants from the New Century Support Foundation for Elitist of Chinese Ministry of Education (NCET-07-0248), the Scientific Foundation for Prominent Youth of Heilongjiang Province, China (JC200717), the Scientific and Technological Project of Heilongjiang Province, China (GC09C407-2) and the National Natural Scientific Foundation of China (30571808, 30872987, 81170431).
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None of the authors claims any conflict of interest exists upon this manuscript.
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Yong-Wei Wang and Shuang-Jia Wang contributed equally to this work.
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Wang, YW., Wang, SJ., Zhou, YN. et al. Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo. J Cancer Res Clin Oncol 138, 785–797 (2012). https://doi.org/10.1007/s00432-012-1152-z
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DOI: https://doi.org/10.1007/s00432-012-1152-z