Skip to main content
SpringerLink
Log in

A ferroptosis-inducing iridium(III) complex

  • Articles
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

Ferroptosis is a recently emerging non-apoptotic mode of cell death involving the production of iron-dependent reactive oxygen species (ROS). Here we described a mitochondria-targeted iridium (III) complex IrFN that exhibited potent antiproliferative activity against a variety of cancer cells, especially the A2780 human ovarian cancer cells, through the ferroptosis pathways. Mechanistic studies by label-free quantitative proteomics profiling indicated that heme oxygenase 1 (HMOX1)-mediated ferroptosis process was activated by IrFN. The study on iron-dependent cell death, ROS accumulation, lipid peroxidation, and over released iron further confirmed the ferroptosis processes. mRNA transcription quantification, in vitro over-expression of HMOX1, and RNAi-mediated knock-down experiments suggested that IrFN activated the over-expression of HMOX1. Our report revealed the first case of anticancer iridium complex leading to ferroptosis, highlighting ferroptosis as a promising approach in future design of metallodrugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rosenberg B, van Camp L, Krigas T. Nature, 1965, 205: 698–699

    Article  CAS  Google Scholar 

  2. Jung Y, Lippard SJ. Chem Rev, 2007, 107: 1387–1407

    Article  CAS  Google Scholar 

  3. Bruijnincx PCA, Sadler PJ. Curr Opin Chem Biol, 2008, 12: 197–206

    Article  CAS  Google Scholar 

  4. Liu Z, Sadler PJ. Acc Chem Res, 2014, 47: 1174–1185

    Article  CAS  Google Scholar 

  5. Guo Z, Sadler PJ. Angew Chem Int Ed, 1999, 38: 1512–1531

    Article  CAS  Google Scholar 

  6. Zou T, Lok CN, Wan PK, Zhang ZF, Fung SK, Che CM. Curr Opin Chem Biol, 2018, 43: 30–36

    Article  CAS  Google Scholar 

  7. Zou T, Lum CT, Lok CN, Zhang JJ, Che CM. Chem Soc Rev, 2015, 44: 8786–8801

    Article  CAS  Google Scholar 

  8. Chen F, Soldevila-Barreda JJ, Romero-Canelón I, Coverdale JPC, Song JI, Clarkson GJ, Kasparkova J, Habtemariam A, Brabec V, Wolny JA, Schünemann V, Sadler PJ. Dalton Trans, 2018, 47: 7178–7189

    Article  CAS  Google Scholar 

  9. Chen F, Romero-Canelón I, Soldevila-Barreda JJ, Song JI, Coverdale JPC, Clarkson GJ, Kasparkova J, Habtemariam A, Wills M, Brabec V, Sadler PJ. Organometallics, 2018, 37: 1555–1566

    Article  CAS  Google Scholar 

  10. Soldevila-Barreda JJ, Romero-Canelón I, Habtemariam A, Sadler PJ. Nat Commun, 2015, 6: 6582

    Article  CAS  Google Scholar 

  11. Coverdale JPC, Romero-Canelón I, Sanchez-Cano C, Clarkson GJ, Habtemariam A, Wills M, Sadler PJ. Nat Chem, 2018, 10: 347–354

    Article  CAS  Google Scholar 

  12. Liu Z, Romero-Canelón I, Qamar B, Hearn JM, Habtemariam A, Barry NPE, Pizarro AM, Clarkson GJ, Sadler PJ. Angew Chem Int Ed, 2014, 53: 3941–3946

    Article  CAS  Google Scholar 

  13. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison Iii B, Stockwell BR. Cell, 2012, 149: 1060–1072

    Article  CAS  Google Scholar 

  14. Gao M, Jiang X. Curr Opin Cell Biol, 2018, 51: 58–64

    Article  CAS  Google Scholar 

  15. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD. Cell, 2017, 171: 273–285

    Article  CAS  Google Scholar 

  16. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. Cell, 2014, 156: 317–331

    Article  CAS  Google Scholar 

  17. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR. eLife, 2014, 3: e02523

    Article  Google Scholar 

  18. Chen Y, Liu Y, Lan T, Qin W, Zhu Y, Qin K, Gao J, Wang H, Hou X, Chen N, Friedmann Angeli JP, Conrad M, Wang C. J Am Chem Soc, 2018, 140: 4712–4720

    Article  CAS  Google Scholar 

  19. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Cell Res, 2016, 26: 1021–1032

    Article  CAS  Google Scholar 

  20. Cairo G, Recalcati S. Expert Rev Mol Med, 2007, 9: 1–13

    Article  Google Scholar 

  21. Kwon MY, Park E, Lee SJ, Chung SW. Oncotarget, 2015, 6: 24393–24403

    PubMed  PubMed Central  Google Scholar 

  22. Chang LC, Chiang SK, Chen SE, Yu YL, Chou RH, Chang WC. Cancer Lett, 2018, 416: 124–137

    Article  CAS  Google Scholar 

  23. Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY, Bayır H, Abhari BA, Angeli JPF, Choi SM, Meul E, Heyninck K, Declerck K, Chirumamilla CS, Lahtela-Kakkonen M, Van Camp G, Krysko DV, Ekert PG, Fulda S, De Geest BG, Conrad M, Kagan VE, Vanden Berghe W, Vandenabeele P, Vanden Berghe T. J Clin Investigation, 2018, 128: 3341–3355

    Article  Google Scholar 

  24. Clark JE, Foresti R, Green CJ, Motterlini R. Biochem J, 2000, 348: 615–619

    Article  CAS  Google Scholar 

  25. Gonzales S, Erario MA, Tomaro ML. Dev Neurosci, 2002, 24: 161–168

    Article  CAS  Google Scholar 

  26. Lanceta L, Li C, Choi AM, Eaton JW. Biochem J, 2013, 449: 189–194

    Article  CAS  Google Scholar 

  27. Song X, Qian Y, Ben R, Lu X, Zhu HL, Chao H, Zhao J. J Med Chem, 2013, 56: 6531–6535

    Article  CAS  Google Scholar 

  28. Wang X, Zhu M, Gao F, Wei W, Qian Y, Liu HK, Zhao J. J Inorg Biochem, 2018, 180: 179–185

    Article  CAS  Google Scholar 

  29. Chang ZY, Coates RM. J Org Chem, 1990, 55: 3464–3474

    Article  CAS  Google Scholar 

  30. Stoll AH, Blakey SB. Chem Sci, 2011, 2: 112–116

    Article  CAS  Google Scholar 

  31. Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Nat Methods, 2009, 6: 359–362

    Article  Google Scholar 

  32. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Mol Cell Proteomics, 2014, 13: 2513–2526

    Article  CAS  Google Scholar 

  33. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh Iii HJ, Kang R, Tang D. Autophagy, 2016, 12: 1425–1428

    Article  CAS  Google Scholar 

  34. Liu HK, Sadler PJ. Acc Chem Res, 2011, 44: 349–359

    Article  CAS  Google Scholar 

  35. Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK. Chem Rev, 2006, 106: 2224–2248

    Article  CAS  Google Scholar 

  36. Merkel AL, Meggers E, Ocker M. Expert Opin Inv Drug, 2012, 21: 425–436

    Article  CAS  Google Scholar 

  37. Hearn JM, Romero-Canelón I, Qamar B, Liu Z, Hands-Portman I, Sadler PJ. ACS Chem Biol, 2013, 8: 1335–1343

    Article  CAS  Google Scholar 

  38. Novohradsky V, Zerzankova L, Stepankova J, Kisova A, Kostrhunova H, Liu Z, Sadler PJ, Kasparkova J, Brabec V. Metallomics, 2014, 6: 1491–1501

    Article  CAS  Google Scholar 

  39. NaveenKumar SK, SharathBabu BN, Hemshekhar M, Kemparaju K, Girish KS, Mugesh G. ACS Chem Biol, 2018, 13: 1996–2002

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21622103, 21671099, 91753121), Shenzhen Basic Research Program (JCYJ20170413150538897, JCYJ20180508182240106), and the Fundamental Research Funds for the Central Universities (020814380109). F. Chen thanks the International Postdoctoral Exchange Fellowship Program of China. We thank the Shanghai Applied Protein Technology Co., Ltd., for technological assistance.

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Coordination Chemistry, Institute of Chemistry and Biomedical Sciences, School of Life Sciences, Nanjing University, Nanjing, 210023, China

    Xiuxiu Wang, Wei Wei & Jing Zhao

  2. School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China

    Xiuxiu Wang, Feng Chen, Jingyi Zhang, Jianxuan Sun, Xinyang Zhao, Yuelu Zhu, Jing Zhao & Zijian Guo

Authors
  1. Xiuxiu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jingyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianxuan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xinyang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuelu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zijian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei Wei, Jing Zhao or Zijian Guo.

Ethics declarations

Conflict of interest The authors declare that they have no conflict of interest.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Chen, F., Zhang, J. et al. A ferroptosis-inducing iridium(III) complex. Sci. China Chem. 63, 65–72 (2020). https://doi.org/10.1007/s11426-019-9577-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-019-9577-3

Keywords

Search

Navigation