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Transition Metal Chemistry

, Volume 43, Issue 2, pp 149–159 | Cite as

A comparative study on in vitro cytotoxicity, cellular uptake, localization and apoptosis-inducing mechanism of two ruthenium(II) complexes

  • Jincan Chen
  • Yao Zhang
  • Baojun Li
  • Guodong Li
  • Xinming Jie
  • Ying Cui
  • Zhilin Zou
  • Xiaofeng Huang
  • Jiaoyue Qu
  • Lanmei Chen
Article
  • 187 Downloads

Abstract

Two ruthenium complexes [Ru(MeIm)4(bpy)]2+ (Ru1, MeIm = 1-methylimidazole, bpy = 2,2′-bipyridine) and [Ru(Im)4(bpy)]2+ (Ru2, Im = imidazole) with the same PF 6 counter-ion but different lipophilicities were synthesized and characterized and as potent anticancer agents. The relationships between cellular uptake, localization and molecular action mechanisms of these complexes were elucidated. The results showed that Ru1 with higher logPo/w exhibited faster cellular uptake rates, but lower anticancer activity than Ru2. In addition, Ru1 predominantly accumulated in the mitochondria and cytoplasm, and induced G0/G1 cell cycle arrest, whereas the more hydrophilic Ru2 tended to localize and accumulate in the cell nucleus and mitochondria. Further mechanism studies indicated that Ru2 caused cell cycle arrest at S phase by regulating cell cycle related proteins and induced apoptosis in A549 cells through DNA damage, cellular ROS accumulation, activation of the caspase pathway and mitochondrial dysfunction.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21701034), Guangdong Provincial Bureau of traditional Chinese Medicine research foundation (No. 20161143), Training Plan of Guangdong Province Outstanding Young Teachers in Higher Education Institutions (No. YQ2015086), the Medical Scientific Research Foundation of Guangdong Province of China (No. A2016464, A2017309, A2016281), the Natural Science Foundation of Guangdong Medical University (No. Z2017001) and the University Student Innovation Experiment Program.

Supplementary material

11243_2018_203_MOESM1_ESM.docx (467 kb)
Supplementary material 1 (DOCX 467 kb)

References

  1. 1.
    Antonarakis ES, Emadi A (2010) Cancer Chemother Pharmacol 66:1–9CrossRefGoogle Scholar
  2. 2.
    Che CM, Huang JS (2002) Coord Chem Rev 231:151–164CrossRefGoogle Scholar
  3. 3.
    Mjos KD, Orvig C (2014) Chem Rev 114:4540–4563CrossRefGoogle Scholar
  4. 4.
    Bergamo A, Sava G (2011) Dalton Trans 40:7817–7823CrossRefGoogle Scholar
  5. 5.
    Bergamo A, Sava G (2007) Dalton Trans 13:1267–1272CrossRefGoogle Scholar
  6. 6.
    Hartinger CG, Jakupec MA, Zorbas SS, Groessl M, Egger A, Berger W, Zorbas H, Dyson PJ, Keppler BK (2008) Chem Biodivers 5:2140–2155CrossRefGoogle Scholar
  7. 7.
    Hotze ACG, Bacac M, Velders AH, Jansen BAJ, Kooijman H, Spek AL, Haasnoot JG, Reedijk J (2003) J Med Chem 46:1743–1750CrossRefGoogle Scholar
  8. 8.
    Scolaro C, Bergamo A, Brescacin L, Delfino R, Cocchietto M, Laurenczy G, Geldbach TJ, Sava G, Dyson PJ (2005) J Med Chem 48:4161–4171CrossRefGoogle Scholar
  9. 9.
    Dyson PJ, Sava G (2006) Dalton Trans 16:1929–1933CrossRefGoogle Scholar
  10. 10.
    Pierroz V, Joshi T, Leonidova A, Mari C, Schur J, Ott I, Spiccia L, Ferrari S, Gasser G (2012) J Am Chem Soc 134:20376–20387CrossRefGoogle Scholar
  11. 11.
    Chen JJ, Luo ZD, Zhao ZN, Xie LN, Zheng WJ, Chen TF (2015) Biomaterials 71:168–177CrossRefGoogle Scholar
  12. 12.
    Ye RR, Ke ZF, Tan CP, He L, Ji LN, Mao ZW (2013) Chem A Eur J 19:10160–10169CrossRefGoogle Scholar
  13. 13.
    Zhao ZN, Luo ZD, Wu Q, Zheng WJ, Feng YX, Chen TF (2014) Dalton Trans 43:17017–17028CrossRefGoogle Scholar
  14. 14.
    Luo ZD, Yu LL, Yang F, Zhao ZN, Yu B, Lai HQ, Wong KH, Ngai SM, Zheng WJ, Chen TF (2014) Metall Integr Biometal Sci 6:1480–1490CrossRefGoogle Scholar
  15. 15.
    Chen LM, Peng F, Li GD, Jie XM, Cai KR, Cai C, Zhong Y, Zeng H, Li W, Zhang Z, Chen JC (2016) J Inorg Biochem 156:64–74CrossRefGoogle Scholar
  16. 16.
    Yang XX, Chen LM, Liu YN, Yang YG, Chen TF, Zheng WJ, Liu J, He QY (2012) Biochimie 94:345–353CrossRefGoogle Scholar
  17. 17.
    Chen LM, Li GD, Peng F, Jie XM, Dongye GZ, Cai KR, Feng RB, Li BJ, Zeng QW, Lun KY, Chen JC, Xu BL (2016) Oncotarget 7:80716–80734Google Scholar
  18. 18.
    Zeng CC, Zhang C, Lai SH, Tang B, Wan D, Liu YJ (2016) Transit Met Chem 41:923–931CrossRefGoogle Scholar
  19. 19.
    Komor AC, Schneider CJ, Weidmann AG, Barton JK (2012) J Am Chem Soc 134:19223–19233CrossRefGoogle Scholar
  20. 20.
    Tan CP, Lai SS, Wu SH, Hu S, Zhou LJ, Chen Y, Wang MX, Zhu YP, Lian W, Peng WL, Ji LN, Xu AL (2010) J Med Chem 53:7613–7624CrossRefGoogle Scholar
  21. 21.
    Wang JQ, Zhang PY, Qian C, Hou XJ, Ji LN, Chao H (2014) J Biol Inorg Chem 19:335–348CrossRefGoogle Scholar
  22. 22.
    Tan CP, Wu SH, Lai SS, Wang MX, Chen Y, Zhou LJ, Zhu YP, Lian W, Peng WL, Ji LN, Xu AL (2011) Dalton Trans 40:8611–8621CrossRefGoogle Scholar
  23. 23.
    Hall MD, Amjadi S, Zhang M, Beale PJ, Hambley TW (2004) J Inorg Biochem 98:1614–1624CrossRefGoogle Scholar
  24. 24.
    Oldfield SP, Hall MD, Platts JA (2007) J Med Chem 50:5227–5237CrossRefGoogle Scholar
  25. 25.
    Nikolic S, Rangasamy L, Gligorijevic N, Arandelovic S, Radulovic S, Gasser G, Grguric-Sipka S (2016) J Inorg Biochem 160:156–165CrossRefGoogle Scholar
  26. 26.
    Schatzschneider U, Niesel J, Ott I, Gust R, Alborzinia H, Wolfl S (2008) ChemMedChem 3:1104–1109CrossRefGoogle Scholar
  27. 27.
    Cao R, Jia JL, Ma XC, Zhou M, Fei H (2013) J Med Chem 56:3636–3644CrossRefGoogle Scholar
  28. 28.
    Puckett CA, Barton JK (2007) J Am Chem Soc 129:46–47CrossRefGoogle Scholar
  29. 29.
    Puckett CA, Barton JK (2008) Biochemistry 47:11711–11716CrossRefGoogle Scholar
  30. 30.
    Puckett CA, Ernst RJ, Barton JK (2010) Dalton Trans 39:1159–1170CrossRefGoogle Scholar
  31. 31.
    Fairbairn DW, Olive PL, O’Neill KL (1995) Mutat Res 339:37–59CrossRefGoogle Scholar
  32. 32.
    Huang HY, Zhang PY, Yu BL, Chen Y, Wang JQ, Ji LN, Chao H (2014) J Med Chem 57:8971–8983CrossRefGoogle Scholar
  33. 33.
    Cadenas E, Davies KJ (2000) Free Radic Biol Med 29:222–230CrossRefGoogle Scholar
  34. 34.
    Ozben T (2007) J Pharm Sci 96:2181–2196CrossRefGoogle Scholar
  35. 35.
    Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Apoptosis 5:415–418CrossRefGoogle Scholar
  36. 36.
    Cattaruzza L, Fregona D, Mongiat M, Ronconi L, Fassina A, Colombatti A, Aldinucci D (2011) Int J Cancer 128:206–215CrossRefGoogle Scholar
  37. 37.
    Florindo PR, Pereira DM, Borralho PM, Rodrigues CM, Piedade MF, Fernandes AC (2015) J Med Chem 58:4339–4347CrossRefGoogle Scholar
  38. 38.
    Qin QP, Chen ZF, Qin JL, He XJ, Li YL, Liu YC, Huang KB, Liang H (2015) Eur J Med Chem 92:302–313CrossRefGoogle Scholar
  39. 39.
    Takahashi A, Alnemri ES, Lazebnik YA, Fernandes-Alnemri T, Litwack G, Moir RD, Goldman RD, Poirier GG, Kaufmann SH, Earnshaw WC (1996) Proc Natl Acad Sci USA 93:8395–8400CrossRefGoogle Scholar
  40. 40.
    Jakupec MA, Nazarov AA, Keppler BK (2008) Organometallics 27:2405–2407CrossRefGoogle Scholar
  41. 41.
    Qian C, Wang JQ, Song CL, Wang LL, Ji LN, Chao H (2013) Metallomics 5:844–854CrossRefGoogle Scholar
  42. 42.
    Lo KK, Lee TK, Lau JS, Poon WL, Cheng SH (2008) Inorg Chem 47:200–208CrossRefGoogle Scholar
  43. 43.
    Du YX, Fu XY, Li H, Chen BL, Guo YH, Su GY, Zhang H, Ning FP, Lin YP, Mei WJ, Chen TF (2014) ChemMedChem 9:714–718CrossRefGoogle Scholar
  44. 44.
    Huang HY, Zhang PY, Ji LN, Chao H (2014) Chem Eur J 21:715–725CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Analysis Centre of Guangdong Medical UniversityZhanjiangChina
  2. 2.Guangdong Key Laboratory for Research and Development of Nature DrugsGuangdong Medical UniversityZhanjiangChina
  3. 3.Dongguan Key Laboratory of Drug Design and Formulation Technology, School of PharmacyGuangdong Medical UniversityDongguanChina
  4. 4.Department of PharmacyGuangdong Food and Drug Vocational CollegeGuangzhouChina

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