Skip to main content
SpringerLink
Log in

A cyclometalated iridium(III) complex induces apoptosis and autophagy through inhibition of the PI3K/AKT/mTOR pathway

  • Published:
Transition Metal Chemistry Aims and scope Submit manuscript

Abstract

An iridium(III) complex [Ir(ppy)2(MHPIP)]PF6 (ppy = 2-phenylpyridine, MHPIP = 2-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-f][1, 10]phenanthroline, Ir-1) was synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The in vitro cytotoxic activities of the free proligand MHPIP and the complex Ir-1 against HepG2, A549, BEL-7402, SGC-7901 and normal LO2 cells were evaluated by the MTT method. MHPIP has no cytotoxic activity toward the selected cell lines, while Ir-1 shows a moderate cytotoxic effect against HepG2. This complex also displays no cytotoxicity against normal LO2 cells, with an IC50 of more than 200 µM. The apoptosis of HepG2 cells induced by the complex was studied with AO/EB and DAPI staining methods, which showed that the complex can effectively induce apoptosis. A comet assay was performed by gel electrophoresis, and the results further show that the complex can cause apoptosis. The level of reactive oxygen species, mitochondrial membrane potential, autophagy, intracellular Ca2+ levels and cell invasion were investigated by fluorescence microscopy, and the cell cycle arrest was studied by flow cytometry. The expression of caspase and Bcl-2 family proteins was investigated by western blot. The results of these experiments indicate that Ir-1 accumulates preferentially in the mitochondria of HepG2 cells and induces apoptosis through inhibition of the PI3K/AKT/mTOR pathway.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) CA Cancer J Clin 61:69–90

    Article  Google Scholar 

  2. Meng XJ, Leyva ML, Jenny M, Gross I, Benosman S, Fricker B, Harlepp S, Hébraud P, Boos A, Wlosik P, Bischoff P, Sirlin C, Pfeffer M, Loeffler JP, Gaiddon C (2009) Cancer Res 69:5458–5466

    Article  CAS  Google Scholar 

  3. Ruiz J, Rodríguez V, Cutillas N, Samper KG, Capdevila M, Palacios Ò, Espinosa A (2012) Dalton Trans 41:12847–12856

    Article  CAS  Google Scholar 

  4. Nagasaka A, Kawane K, Yoshida H, Nagata S (2010) Cell Death Differ 17:931–941

    Article  CAS  Google Scholar 

  5. Burgess DJ (2013) Nat Rev Cancer 13:79

    Article  CAS  Google Scholar 

  6. Zimmermann KC, Bonzon C, Green DR (2001) Pharmacol Ther 92:57–70

    Article  CAS  Google Scholar 

  7. Klionsky DJ, Emr SD (2000) Science 290:1717–1721

    Article  CAS  Google Scholar 

  8. Zhang Y, Yang JW, Ren X, Yang JM (2011) Autophagy 7:1557–1558

    Article  CAS  Google Scholar 

  9. Li Y, Zhu H, Zeng X, Fan J, Qian X, Wang S, Wang Z, Sun Y, Wang X, Wang W, Ju D (2013) Mol Neurobiol 47:1000–1010

    Article  CAS  Google Scholar 

  10. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Cell Death Differ 16:966–975

    Article  CAS  Google Scholar 

  11. Song X, Kim SY, Zhang L, Tang D, Bartlett DL, Kwon YT, Lee YJ (2014) Cell Death Dis 5:e1504

    Article  CAS  Google Scholar 

  12. Zhang M, Harashima N, Moritani T, Huang W, Harada M (2015) PLoS ONE 10:e0127386

    Article  Google Scholar 

  13. Qin G, Wu L, Liu H, Pang Y, Zhao C, Wu S, Wang X, Chen T (2015) Exp Cell Res 336:308–317

    Article  CAS  Google Scholar 

  14. Li YC, He SM, He ZX, Li M, Yang Y, Pang JX (2014) Cancer Lett 344:239–259

    Article  CAS  Google Scholar 

  15. Wan D, Tang B, Wang YJ, Guo BH, Yin H, Yi QY, Liu YJ (2017) Eur J Med Chem 139:180–189

    Article  CAS  Google Scholar 

  16. Chen H, Li Z, Han Y (2000) J Agric Food Chem 48:5312–5315

    Article  CAS  Google Scholar 

  17. Meazza G, Bettarini F, Porta LP, Piccardi P, Signorini E, Portoso D, Fornara L (2004) Pest Manag Sci 60:1178–1188

    Article  CAS  Google Scholar 

  18. Park H, Lee K, Park S, Ahn B, Lee J, Cho HY, Lee K (2005) Bioorg Med Chem Lett 15:3307–3312

    Article  CAS  Google Scholar 

  19. Bekhit AA, Ashour HMA, Guemei AA (2005) Arch Pharm 2338:167–174

    Article  Google Scholar 

  20. Sprouse S, King KA, Spellane PJ, Watts RJ (1984) J Am Chem Soc 106:6647–6653

    Article  CAS  Google Scholar 

  21. Lai SH, Jiang GB, Yao JH, Li W, Han BJ, Zhang C, Zeng CC, Liu YJ (2015) J Inorg Biochem 152:1–9

    Article  CAS  Google Scholar 

  22. Lo KK, Lee TK, Lau JS, Poon WL, Cheng SH (2008) Inorg Chem 47:200–208

    Article  CAS  Google Scholar 

  23. Contento AL, Xiong Y, Bassham DC (2005) Plant J 42:598–608

    Article  CAS  Google Scholar 

  24. Chen TF, Wong YS (2008) Cell Mol Life Sci 65:2763–2775

    Article  CAS  Google Scholar 

  25. Bai F, Ni B, Liu M, Feng Z, Xiong Q, Shao G (2015) Vet Microbiol 175:58–67

    Article  CAS  Google Scholar 

  26. Li GY, Du KJ, Wang JQ, Liang JW, Kou JF, Hou XJ, Ji LN, Chao H (2013) J Inorg Biochem 119:43–53

    Article  CAS  Google Scholar 

  27. Alapetite C, Wachter T, Sage E, Moustacchi E (1996) Int J Radiat Biol 69:359–369

    Article  CAS  Google Scholar 

  28. Bartels RH, Van der Linden YM, Van der Graaf WT (2008) CA Cancer J Clin 58:245–259

    Article  Google Scholar 

  29. Shapiro GI, Harper JW (1999) J Clin Invest 104:1645–1653

    Article  CAS  Google Scholar 

  30. Wang D, Lippard SJ (2005) Nat Rev Drug Discov 4:307–320

    Article  CAS  Google Scholar 

  31. Singh T, Sharma SD, Katiyar SK (2011) PLoS ONE 6:e27444

    Article  CAS  Google Scholar 

  32. Crompton M (1999) Biochem J 341:233–249

    Article  CAS  Google Scholar 

  33. Halestrap AP, Clarke SJ, Javadov SA (2004) Cardiovasc Res 61:372–385

    Article  CAS  Google Scholar 

  34. Laver DR (2007) Biophys J 92:3541–3555

    Article  CAS  Google Scholar 

  35. Deretic V (2011) Immunol Rev 240:92–104

    Article  CAS  Google Scholar 

  36. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Nature 451:1069–1075

    Article  CAS  Google Scholar 

  37. Shintani T, Klionsky DJ (2004) Science 306:990–995

    Article  CAS  Google Scholar 

  38. Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) Nat Rev Cancer 5:726–734

    Article  CAS  Google Scholar 

  39. Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, Gelovani J, Krishnan S, Guha S, Aggarwal BB (2010) Int J Cancer 127:257–268

    CAS  Google Scholar 

  40. Schmitz KJ, Ademi C, Bertram S, Schmid KW, Baba HA (2016) World J Surg Oncol 14:189

    Article  Google Scholar 

  41. Maejima Y, Isobe M, Sadoshima J (2016) J Mol Cell Cardiol 95:19–25

    Article  CAS  Google Scholar 

  42. Huang X, Bai HM, Chen L, Li B, Lu YC (2010) J Clin Neurosci 17:1515–1519

    Article  CAS  Google Scholar 

  43. Apel K, Hirt H (2004) Annu Rev Plant Biol 55:373–399

    Article  CAS  Google Scholar 

  44. Khan AU, Wilson T (1995) Chem Biol 2:437–445

    Article  CAS  Google Scholar 

  45. Dougan SJ, Habtemariam A, McHale SE, Parsons S, Sadler PJ (2008) Proc Natl Acad Sci USA 105:11628–11633

    Article  CAS  Google Scholar 

  46. Fu Y, Romero MJ, Habtemariam A, Snowden ME, Song LJ, Clarkson GJ, Qamar B, Pizarro AM, Unwin PR, Sadler PJ (2012) Chem Sci 3:2485–2494

    Article  CAS  Google Scholar 

  47. Fu Y, Habtemariam A, Pizarro AM, Van Rijt SH, Healey DJ, Cooper PA, Shnyder SD, Clarkson GY, Sadler PJ (2010) J Med Chem 53:8192–8196

    Article  CAS  Google Scholar 

  48. Tang B, Wan D, Lai SH, Yang HH, Zhang C, Wang XZ, Zeng CC, Liu YJ (2017) J Inorg Biochem 173:93–104

    Article  CAS  Google Scholar 

  49. Wan D, Lai SH, Zeng CC, Zhang C, Tang B, Liu YJ (2017) J Inorg Biochem 173:1–11

    Article  CAS  Google Scholar 

  50. Tang B, Han BJ, Wan D, Lai SH, Wang XZ, Zhang C, Zeng CC, Liu YJ (2017) Transit Met Chem 42:373–386

    Article  CAS  Google Scholar 

  51. Duriez PJ, Shah GM (1997) Biochem Cell Biol 75:337–349

    Article  CAS  Google Scholar 

  52. Taylor RC, Cullen SP, Martin SJ (2008) Nat Rev Mol Cell Biol 9:231–241

    Article  CAS  Google Scholar 

  53. Estaquier J, Vallette F, Vayssiere JL, Mignotte B (2012) Adv Exp Med Biol 942:157–183

    Article  CAS  Google Scholar 

  54. Rodon J, Dienstmann R, Serra V, Tabernero J (2013) Nat Rev Clin Oncol 10:143–153

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Natural Science Foundation of Guangdong Province (No. 2016A030313728) and Jiangxi University of Technology for financial support.

Author information

Authors and Affiliations

  1. School of Nursing, Jiangxi University of Technology, Nanchang, 330098, Jiangxi, People’s Republic of China

    Zhen-Hua Liang

  2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Dan Wan, Qiao-Yan Yi, Wen-Yao Zhang & Yun-Jun Liu

Authors
  1. Zhen-Hua Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiao-Yan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Yao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun-Jun Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, ZH., Wan, D., Yi, QY. et al. A cyclometalated iridium(III) complex induces apoptosis and autophagy through inhibition of the PI3K/AKT/mTOR pathway. Transit Met Chem 43, 243–257 (2018). https://doi.org/10.1007/s11243-018-0210-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11243-018-0210-z

Search

Navigation