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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

SCLC:

Small cell lung cancer

NSCLC:

Non-small cell lung cancer

FDA:

Food and Drug Administration

MMP:

Mitochondrial membrane potential

CI:

Combination index

References

  1. 1.

    Chen WQ, Zheng RS, Zeng HM, Zhang SW (2015) Epidemiology of lung cancer in China. Thorac Cancer 6(2):209–215

    Article  Google Scholar 

  2. 2.

    Oser MG, Niederst MJ, Sequist LV, Engelman JA (2015) Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 16(4):E165–E172

    CAS  Article  Google Scholar 

  3. 3.

    Gazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17(12):725–737

    CAS  Article  Google Scholar 

  4. 4.

    Pietanza MC, Byers LA, Minna JD, Rudin CM (2015) Small cell lung Cancer: will recent Progress Lead to improved outcomes? Clin Cancer Res 21(10):2244–2255

    CAS  Article  Google Scholar 

  5. 5.

    Hong B, Wang HG, Deng K, Wang W, Dai HM, Lui VWY, Lin WC (2017) Combination treatment of RAD001 and BEZ235 exhibits synergistic antitumor activity via down-regulation of p-4E-BP1/Mcl-1 in small cell lung cancer. Oncotarget 8(63):106486–106498

    Article  Google Scholar 

  6. 6.

    Adhireksan Z, Palermo G, Riedel T, Ma ZJ, Muhammad R, Rothlisberger U, Dyson PJ, Davey CA (2017) Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nat Commun 8:14860

  7. 7.

    Chen X, Yang QQ, Xiao L, Tang DL, Dou QP, Liu JB (2017) Metal-based proteasomal deubiquitinase inhibitors as potential anticancer agents. Cancer Metastasis Rev 36(4):655–668

    CAS  Article  Google Scholar 

  8. 8.

    Li H, Hu J, Wu SH, Wang L, Cao XB, Zhang XS, Dai BB, Cao MR, Shao RP, Zhang R, Majidi M, Ji L, Heymach JV, Wang M, Pan SY, Minna J, Mehran RJ, Swisher SG, Roth JA, Fang BL (2016) Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget 7(3):3548–3558

    PubMed  Google Scholar 

  9. 9.

    Debnath A, Parsonage D, Andrade RM, He C, Cobo ER, Hirata K, Chen S, Garcia-Rivera G, Orozco E, Martinez MB, Gunatilleke SS, Barrios AM, Arkin MR, Poole LB, McKerrow JH, Reed SL (2012) A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nat Med 18(6):956–960

    CAS  Article  Google Scholar 

  10. 10.

    Wang HG, Hong B, Li XM, Deng K, Li H, Lui VWY, Lin WC (2017) JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer. Oncotarget 8(49):86312–86324

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Ashton JC (2015) Drug combination studies and their synergy quantification using the Chou-Talalay method-letter. Cancer Res 75(11):2400–2400

    CAS  Article  Google Scholar 

  12. 12.

    Zou P, Chen MX, Ji JS, Chen WQ, Chen X, Ying SL, Zhang JR, Zhang ZH, Liu ZG, Yang SL, Liang G (2015) Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget 6(34):36505–36521

    Article  Google Scholar 

  13. 13.

    Wang H, Bouzakoura S, De Mey S, Jiang H, Law K, Dufait I, Corbet C, Verovski V, Gevaert T, Feron O, Van den Berge D, Storme G, De Ridder M (2017) Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species. Oncotarget 8(22):35728–35742

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Shaw CF (1999) Gold-based therapeutic agents. Chem Rev 99(9):2589–2600

    CAS  Article  Google Scholar 

  15. 15.

    Liu CR, Liu Z, Li M, Li XL, Wong YS, Ngai SM, Zheng WJ, Zhang YB, Chen TF (2013) Enhancement of Auranofin-induced apoptosis in MCF-7 human breast cells by Selenocystine, a synergistic inhibitor of Thioredoxin reductase. PLoS One 8(1):e53945

    CAS  Article  Google Scholar 

  16. 16.

    Lee JE, Kwon YJ, Baek HS, Ye DJ, Cho E, Choi HK, Oh KS, Chun YJ (2017) Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. Arch Pharm Res 40(6):746–759

    CAS  Article  Google Scholar 

  17. 17.

    Wangpaichitr M, Wu C, You M, Maher JC, Dinh V, Feun LG, Savaraj N (2009) N',N'-dimethyl-N',N'-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) selectively kills cisplatin resistant lung Cancer cells through reactive oxygen species (ROS). Cancers 1(1):23–38. https://doi.org/10.3390/cancers1010023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Yang JC, Lu MC, Lee CL, Chen GY, Lin YY, Chang FR, Wu YC (2011) Selective targeting of breast cancer cells through ROS-mediated mechanisms potentiates the lethality of paclitaxel by a novel diterpene, gelomulide K. Free Radic Biol Med 51(3):641–657

    CAS  Article  Google Scholar 

  19. 19.

    Luo M, Shang L, Brooks MD, Jiagge E, Zhu YY, Buschhaus JM, Conley S, Fath MA, Davis A, Gheordunescu E, Wang YF, Harouaka R, Lozier A, Triner D, McDermott S, Merajver SD, Luker GD, Spitz DR, Wicha MS (2018) Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metab 28(1):69–86. https://doi.org/10.1016/j.cmet.2018.06.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Yan X, Zhang X, Wang L, Zhang R, Pu X, Wu S, Li L, Tong P, Wang J, Meng QH, Jensen VB, Girard L, Minna JD, Roth JA, Swisher SG, Heymach JV, Fang B (2019) Inhibition of Thioredoxin/Thioredoxin reductase induces synthetic lethality in lung cancers with compromised glutathione homeostasis. Cancer Res 79(1):125–132. https://doi.org/10.1158/0008-5472.CAN-18-1938

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Hatem E, Azzi S, El Banna N, He T, Heneman-Masurel A, Vernis L, Baille D, Masson V, Dingli F, Loew D, Azzarone B, Eid P, Baldacci G, Huang ME (2018) Auranofin/vitamin C: a novel drug combination targeting triple-negative breast Cancer. J Natl Cancer Inst. https://doi.org/10.1093/ije/djy149

  22. 22.

    Ren G, Sha T, Guo J, Li W, Lu J, Chen X (2015) Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells. J Nat Med 69(4):522–530. https://doi.org/10.1007/s11418-015-0918-4

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Fiskus W, Saba N, Shen M, Ghias M, Liu J, Gupta SD, Chauhan L, Rao R, Gunewardena S, Schorno K, Austin CP, Maddocks K, Byrd J, Melnick A, Huang P, Wiestner A, Bhalla KN (2014) Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res 74(9):2520–2532. https://doi.org/10.1158/0008-5472.CAN-13-2033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Chiu WH, Luo SJ, Chen CL, Cheng JH, Hsieh CY, Wang CY, Huang WC, Su WC, Lin CF (2012) Vinca alkaloids cause aberrant ROS-mediated JNK activation, Mcl-1 downregulation, DNA damage, mitochondrial dysfunction, and apoptosis in lung adenocarcinoma cells. Biochem Pharmacol 83(9):1159–1171. https://doi.org/10.1016/j.bcp.2012.01.016

    CAS  Article  PubMed  Google Scholar 

Download references

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..

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Bo Hong or Wenchu Lin.

Ethics declarations

Conflict of interest

Authors have no financial/commercial conflicts of interest regarding the study.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Small cell lung cancer
  • Ciplatin
  • Auranofin
  • ROS
  • DNA damage