Skip to main content
SpringerLink
Log in

Induction of apoptosis in SGC-7901 cells by ruthenium(II) complexes through ROS-mediated lysosome–mitochondria dysfunction and inhibition of PI3K/AKT/mTOR pathways

  • Published:
Transition Metal Chemistry Aims and scope Submit manuscript

Abstract

Five Ru(II) polypyridyl complexes [Ru(N–N)2(nfip)](ClO4)2 (N–N = dmb, 1; bpy, 2; ttbpy, 3, phen, 4, dmp, 5) were synthesized and characterized. The cytotoxic activities of the complexes against cancer SGC-7901, Eca-109, HepG2, A549, HeLa and normal LO2 cells were investigated using the MTT method. Complexes 1–4 show high cytotoxicity against SGC-7901 cells with low IC50 values of 12.4 ± 1.4, 6.7 ± 1.6, 1.3 ± 0.5 and 1.1 ± 0.4 µM, respectively. Complex 5 is active against HeLa cells with an IC50 value of 2.2 ± 0.6 µM. Among these complexes, complexes 3 and 4 exhibit higher cytotoxic activity than cisplatin toward SGC-7901 cells under identical conditions. Apoptosis was assayed using the AO/EB staining method and flow cytometry. The location of the complexes at lysosomes and mitochondria, the permeability of lysosomes, the levels of reactive oxygen species, and the changes of mitochondrial membrane potential were studied by fluorescence microscopy. The cell cycle distribution of SGC-7901 cells induced by the complexes was studied by flow cytometry. The expression of caspase-3, PARP and Bcl-2 family proteins was investigated by Western blot. The complexes were shown to accumulate in the lysosomes and then enter into the mitochondria. The mechanism demonstrates that the complexes induce apoptosis in SGC-7901 cells through three pathways: (1) ROS-mediated lysosomal–mitochondrial dysfunction; (2) inhibition of PI3K/AKT/mTOR pathway; and (3) DNA damage and inhibition of the cell growth at G0/G1 or S phase.

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. Boerner LJ, Zaleski JM (2005) Curr Opin Chem Biol 9:135–144

    Article  CAS  PubMed  Google Scholar 

  2. Palermo G, Magistrato A, Riedel T, Von Erlach T, Davey CA, Dyson PJ, Rothlisberger U (2015) ChemMedChem 11:1199–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Markman M (2003) Expert Opin Drug Saf 2:597–607

    Article  CAS  PubMed  Google Scholar 

  4. Bruijnincx PC, Sadler PJ (2008) Curr Opin Chem Biol 12:197–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen JC, Peng F, Zhang Y, Li BJ, She J, Jia XM, Zou ZL, Chen M, Chen LM (2017) Eur J Med Chem 140:104–117

    Article  CAS  PubMed  Google Scholar 

  6. Kaulage MH, Maji B, Pasadi S, Buattacharya S, Muniyappa K (2017) Eur J Med Chem 139:1016–1029

    Article  CAS  PubMed  Google Scholar 

  7. Wan D, Tang B, Wang YJ, Guo BH, Yin H, Yi QY, Liu YJ (2017) Eur J Med Chem 139:180–190

    Article  CAS  PubMed  Google Scholar 

  8. Zeng CC, Lai SH, Yao JH, Zhang C, Yin H, Li W, Han BJ, Liu YJ (2016) Eur J Med Chem 122:118–126

    Article  CAS  PubMed  Google Scholar 

  9. Wang JQ, Kou JF, Zhao ZZ, Qiu KQ, Chao H (2017) Inorg Chem Front 4:1003–1012

    Article  CAS  Google Scholar 

  10. Cao Q, Li Y, Freisinger E, Qin PZ, Sigel RO, Mao ZW (2017) Inorg Chem Front 4:10–32

    Article  CAS  Google Scholar 

  11. Deepika N, Kumar YP, Devi CS, Reddy PV, Srishailam A, Satyanarayana S (2013) J Biol Inorg Chem 18:751–766

    Article  CAS  PubMed  Google Scholar 

  12. Zhang C, Han BJ, Zeng CC, Tang B, Wan D, Jiang GB, Liu YJ (2016) J Inorg Biochem 157:62–72

    Article  CAS  PubMed  Google Scholar 

  13. Sainuddin T, McCain J, Pinto M, Yin H, Gibson J, Hetu M, McFarland SA (2016) Inorg Chem 55:83–95

    Article  CAS  PubMed  Google Scholar 

  14. Oliveira KM, Liany LD, Corrêa RS, Deflon VM, Comineth MR, Bitastia AA (2017) J Inorg Biochem 176:66–76

    Article  CAS  PubMed  Google Scholar 

  15. Chen WX, Song XD, Hu SF, Sun J, Chen JX, Wu T, Mao ZW (2016) J Inorg Biochem 64:91–98

    Article  CAS  Google Scholar 

  16. Milutinović MM, Rilak A, Bratsos L, Klisurić O, Vraneŝ M, Gligorijević N, Radelović S, Bugarčić ŻD (2017) J Inorg Biochem 169:1–12

    Article  CAS  PubMed  Google Scholar 

  17. Li GY, Sun LL, Ji LN, Chao H (2016) Dalton Trans 45:13261–13276

    Article  CAS  PubMed  Google Scholar 

  18. Du KJ, Liang JW, Kou JF, Qian C, Ji LN, Chao H (2014) Dalton Trans 43:17303–17316

    Article  CAS  PubMed  Google Scholar 

  19. Tang B, Han BJ, Wan D, Lai SH, Wang XZ, Zhang C, Zeng CC, Liu YJ (2017) Transit Met Chem 42:373–396

    Article  CAS  Google Scholar 

  20. Li W, Jiang GB, Yao JH, Wang XZ, Wang J, Han BJ, Xie YY, Lin GJ, Huang HL, Liu YJ (2014) J Photochem Photobiol B Biol 140:94–104

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. 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  PubMed  Google Scholar 

  23. Cao WQ, Zheng WJ, Chen TF (2015) Sci Rep 5:9157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Deepika N, Devi CS, Kumar YP, Reddy KL, Reddy PV, Kumar DA, Singh SS, Satyanarayana S (2016) J Photochem Photobiol B Biol 160:142–153

    Article  CAS  Google Scholar 

  25. Juris A, Balzani V, Barigelletti F, Campagna S, Belser P, Von Zelewsky A (1988) Coord Chem Rev 84:85–277

    Article  CAS  Google Scholar 

  26. Habtemariam A, Melchart M, Fernandez R, Parsons S, Oswald IDH, Parkin A, Fabbiani FPA, Davidson JE, Dawson AE, Aird RE, Jodrell DI, Sadler PJ (2006) J Med Chem 49:6858–6868

    Article  CAS  PubMed  Google Scholar 

  27. Sun B, Wang YC, Qian C, Chu J, Liang SM, Chao H, Ji LN (2010) J Mol Struct 963:153–159

    Article  CAS  Google Scholar 

  28. Sullivan BP, Salmon DJ, Meyer TJ (1978) Inorg Chem 17:3334–3341

    Article  CAS  Google Scholar 

  29. Collin JP, Sauvage JP (1986) Inorg Chem 25:135–141

    Article  CAS  Google Scholar 

  30. Mosmann T (1983) J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Alapetite C, Wachter T, Sage E, Moustacchi E (1986) Int J Radiat Biol 69:359–369

    Article  Google Scholar 

  33. Franco JL, Posser T, Dunkley PR (2009) Free Radic Biol Med 7:449–457

    Article  CAS  Google Scholar 

  34. Wang X, Nguyen DM, Yanez CO, Rodriguez L, Ahn HY, Bondar MV, Belfield KD (2010) J Am Soc Chem 132:12237–12239

    Article  CAS  Google Scholar 

  35. Chang Y, Li Y, Ye N, Guo X, Li Z, Sun G, Sun Y (2016) Apoptosis 21:977–996

    Article  CAS  PubMed  Google Scholar 

  36. Zhong Y, Jin C, Gan J, Wang X, Shi Z, Xia X, Peng X (2017) Toxicon 137:106–113

    Article  CAS  PubMed  Google Scholar 

  37. Yugandhar D, Nayak VL, Archana S, Shekar KC, Srivastava AK (2015) Eur J Med Chem 101:348–357

    Article  CAS  PubMed  Google Scholar 

  38. Prasad S, Gupta SC, Tyagi AK (2017) Cancer Lett 387:95–105

    Article  CAS  PubMed  Google Scholar 

  39. Ozben T (2007) J Pharm Sci 96:2181–2196

    Article  CAS  PubMed  Google Scholar 

  40. Shadel GS, Horvath TL (2015) Cell 163:560–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gammella E, Recalcati S, Cairo G (2016) Oxid Med Cell Longev 2016:8629024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Diebold L, Chandel NS (2016) Free Radic Biol Med 100:86–93

    Article  CAS  PubMed  Google Scholar 

  43. Zorov DB, Juhaszova M, Sollott SJ (2014) Physiol Rev 94:909–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shen HM, Liu ZG (2006) Free Radic Biol Med 40:928–939

    Article  CAS  PubMed  Google Scholar 

  45. Dröge W (2002) Physiol Rev 82:47–95

    Article  PubMed  Google Scholar 

  46. Romagnoli A, Aguiari P, De SD, Leo S, Marchi S, Rimessi A, Zecchini E, Pinton P, Rizzuto R (2007) Endoplasmic reticulum/mitochondria calcium cross-talk. Novartis Found Symp 287:122–131

    CAS  PubMed  Google Scholar 

  47. Duszyński J, Kozieł R, Brutkowski W, Szczepanowska J, Zabłocki K (2006) BBA Bioenerg 1757:380–387

    Article  CAS  Google Scholar 

  48. Trump BF, Berezesky IK (1995) FASEB J 9:219–228

    Article  CAS  PubMed  Google Scholar 

  49. Orrenius S, Zhivotovsky B, Nicotera P, Orrenius S, Zhivotovsky B, Nicotera P (2003) Nat Rev Mol Cell Biol 4:552–565

    Article  CAS  PubMed  Google Scholar 

  50. Renz A, Berdel WE, Kreuter M, Belka C, Schulze-Osthoff K, Los M (2001) Blood 98:1542–1548

    Article  CAS  PubMed  Google Scholar 

  51. Osaka A, Hasegawa H, Yamada Y, Yanagihara K, Hayashi T, Mine M, Aoyama M, Sawada T, Kamihira SA (2009) J Cancer Res Clin Oncol 135:371–377

    Article  CAS  PubMed  Google Scholar 

  52. Alghamian Y, Abou AG, Murad H, Madania A (2017) Adv Med Sci 62:330–337

    Article  PubMed  Google Scholar 

  53. Okada H, Mak TW (2004) Nat Rev Cancer 4:592–603

    Article  CAS  PubMed  Google Scholar 

  54. Tiwari RV, Parajuli P, Sylvester PW (2015) Mol Cell Biochem 408:1–15

    Article  CAS  Google Scholar 

  55. Biederbick A, Kern HF, Elsässer HP (1995) Eur J Cell Biol 66:3–14

    CAS  PubMed  Google Scholar 

  56. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Nat Rev Drug Discov 6:304–312

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Hara K, Kasahara E, Takahashi N, Konishi M, Inoue J, Jikumaru M, Kubo S, Okamura H, Sato E, Inoue M (2011) J Pharmacol Exp Ther 337:838–845

    Article  CAS  PubMed  Google Scholar 

  59. Danial NN, Korsmeyer SJ (2004) Cell 116:205–219

    Article  CAS  PubMed  Google Scholar 

  60. Kilic U, Caglayan AB, Beker MC, Gunal MY, Caglayan B, Yalcin E, Kelestemur T, Gundogdu RZ, Yulug B, Yılmaz B, Kerman BE, Kilic E (2017) Redox Biol 12:657–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tapia-Limonchi R, Cahuana GM, Caballano-Infantes E, Salguero-Aranda C, Beltran-Povea A, Hitos AB, Hmadcha A, Martin F, Soria B, Bedoya FJ, Tejedo JR (2016) J Cell Biochem 117:2078–2088

    Article  CAS  PubMed  Google Scholar 

  62. Song G, Ouyang G, Bao S (2005) J Cell Mol Med 9:59–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Nature Science Foundation of China (No. 21877018) and the Natural Science Foundation of Guangdong Province (No. 2016A030313728).

Author information

Authors and Affiliations

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

    Qiao-Yan Yi, Yang-Jie Wang, Miao He, Wen-Yao Zhang, Fan Du, Yi-Ying Gu, Lan Bai & Yun-Jun Liu

Authors
  1. Qiao-Yan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang-Jie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miao He
    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. Fan Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Ying Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lan Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun-Jun Liu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1027 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yi, QY., Wang, YJ., He, M. et al. Induction of apoptosis in SGC-7901 cells by ruthenium(II) complexes through ROS-mediated lysosome–mitochondria dysfunction and inhibition of PI3K/AKT/mTOR pathways. Transit Met Chem 44, 187–205 (2019). https://doi.org/10.1007/s11243-018-0283-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11243-018-0283-8

Search

Navigation