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A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer

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Summary

Small cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SCLC cells, which was accompanied by the enhanced induction of cell cycle arrest and apoptosis. The synergistic action of auranofin and cisplatin was through ROS overproduction, thereby leading to mitochondrial dysfunction and DNA damage. Furthermore, in vivo study demonstrated that the combination treatment of auranofin and cisplatin dramatically inhibited tumor growth in SCLC. Therefore, our study provides a rational basis for further clinical study to test whether auranofin could enhance the sensitivity of cisplatin-based therapy in SCLC patients.

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Abbreviations

SCLC:

Small cell lung cancer

NSCLC:

Non-small cell lung cancer

FDA:

Food and Drug Administration

MMP:

Mitochondrial membrane potential

CI:

Combination index

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Acknowledgements

This study was supported by National Natural Science Foundation of China (Grant Numbers: 81872438, 81672647, 81502632), Natural Science Foundation of Anhui Province (Grant Number: 1608085MH179), Science and Technology Major Project of Anhui Province (Grant Number: 18030801140), Science and Technology Service Network Initiative of Chinese Academy of Sciences (Grant Number: KFJ-STS-SCYD-010), Key program of 13th five-year plan of CASHIPS (Grant Number: KP-2017-26), and the 100-Talent Program of Chinese Academy of Sciences.

Funding

This study was supported by National Natural Science Foundation of China (Grant Numbers: 81872438, 81672647, 81502632), Natural Science Foundation of Anhui Province (Grant Number: 1608085MH179), Science and Technology Major Project of Anhui Province (Grant Number: 18030801140), Science and Technology Service Network Initiative of Chinese Academy of Sciences (Grant Number: KFJ-STS-SCYD-010), Key program of 13th five-year plan of CASHIPS (Grant Number: KP-2017-26), and the 100-Talent Program of Chinese Academy of Sciences..

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Authors and Affiliations

  1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, People’s Republic of China

    Xiaoli Liu, Wei Wang, Yanping Yin, Ming Li, Hong Li, Hang Xiang, Bo Hong & Wenchu Lin

  2. University of Science and Technology of China, Hefei, 230036, Anhui, People’s Republic of China

    Xiaoli Liu, Yanping Yin, Ming Li & Hang Xiang

  3. Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, People’s Republic of China

    Xiaoli Liu, Wei Wang, Yanping Yin, Ming Li, Hong Li, Hang Xiang, Bo Hong & Wenchu Lin

  4. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China

    Ao Xu & Xiaodong Mei

Authors
  1. Xiaoli Liu
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  2. Wei Wang
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  3. Yanping Yin
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  4. Ming Li
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  5. Hong Li
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  7. Ao Xu
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  8. Xiaodong Mei
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  9. Bo Hong
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  10. Wenchu Lin
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Correspondence to Bo Hong or Wenchu Lin.

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Liu, X., Wang, W., Yin, Y. et al. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Invest New Drugs 37, 1166–1176 (2019). https://doi.org/10.1007/s10637-019-00750-2

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