BH3 Mimetic ABT-199 Enhances the Sensitivity of Gemcitabine in Pancreatic Cancer in vitro and in vivo

Abstract

Background and Aims

Pancreatic cancer is an aggressive malignancy with poor prognosis. Gemcitabine is the standard chemotherapeutic drug used to treat the disease; however, it has a low response rate. Therefore, there is an urgent need to develop new and safe therapies to enhance sensitivity to gemcitabine in treating pancreatic cancer.

Methods

The synergistic effect of gemcitabine combined with specific B cell CLL/lymphoma 2 (Bcl-2) inhibitor ABT-199 against pancreatic cancer was tested using cell viability, cell cycle, and apoptosis assays in vitro and in an MIA Paca-2 xenograft model in vivo. Its underlying mechanism was explored using western blotting analysis of Bcl-2 family proteins.

Results

ABT-199 not only enhanced the effect of gemcitabine on cell growth inhibition but also promoted gemcitabine-induced apoptosis in pancreatic cancer cell lines. Gemcitabine decreased the expression of anti-apoptotic protein Mcl-1 but increased the expression of anti-apoptotic protein Bcl-2. ABT-199 downregulated the gemcitabine-induced production of Bcl-2 and increased the expression of pro-apoptotic protein Bcl-2 interacting protein (BIM). Mouse xenograft experiments also confirmed the synergistic effect of gemcitabine and ABT-199 on tumor growth inhibition and the induction of tumor cell apoptosis.

Conclusion

Our results indicated that ABT-199 improved the anti-tumor effect of gemcitabine on pancreatic cancer by downregulating gemcitabine-induced overexpression of Bcl-2. ABT-199 has already been investigated in phase 3 clinical trials for chronic lymphocytic leukemia; therefore, it may serve as a potential drug to improve the sensitivity of pancreatic cancer to gemcitabine.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81572308, 81702306, 81871934) and Science and Technology Commission of Shanghai Municipality (Grant No. 16411952300).

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Correspondence to Ruyi Xue or Wenqing Tang or Shuncai Zhang.

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The authors declare that they have no conflict of interest.

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Zhou, Y., Liu, H., Xue, R. et al. BH3 Mimetic ABT-199 Enhances the Sensitivity of Gemcitabine in Pancreatic Cancer in vitro and in vivo. Dig Dis Sci 63, 3367–3375 (2018). https://doi.org/10.1007/s10620-018-5253-7

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Keywords

  • Pancreatic cancer
  • Gemcitabine
  • ABT-199
  • Apoptosis
  • Combination therapy