JBIC Journal of Biological Inorganic Chemistry

, Volume 18, Issue 2, pp 249–260 | Cite as

Influence of extracellular pH on the cytotoxicity, cellular accumulation, and DNA interaction of novel pH-sensitive 2-aminoalcoholatoplatinum(II) complexes

  • Seied Mojtaba Valiahdi
  • Alexander E. Egger
  • Walter Miklos
  • Ute Jungwirth
  • Kristof Meelich
  • Petra Nock
  • Walter Berger
  • Christian G. Hartinger
  • Markus Galanski
  • Michael A. Jakupec
  • Bernhard K. Keppler
Original Paper


Extracellular acidity is a frequent pathophysiological condition of solid tumors offering possibilities for improving the tumor selectivity of molecular therapy. This might be accomplished by prodrugs with low systemic toxicity, attaining their full antitumor potency only under acidic conditions, such as bis(2-aminoalcoholato-κ²N,O)platinum(II) complexes that are activated by protonation of alcoholato oxygen, resulting in cleavage of platinum–oxygen bonds. In this work, we examined whether the pH dependency of such compounds is reflected in differential biological activity in vitro. In particular, the pH dependence of cytotoxicity, cellular accumulation, DNA platination, GMP binding, effects on DNA secondary structure, cell cycle alterations, and induction of apoptosis was investigated. Enhanced cytotoxicity of five of these complexes in non-small-cell lung cancer (A549) and colon carcinoma (HT-29) cells at pH 6.0 in comparison with pH 7.4 was confirmed: 50 % growth inhibition concentrations ranged from 42 to 214 μM in A549 cells and from 35 to 87 μM in HT-29 cells at pH 7.4 and decreased at pH 6.0 to 11–50 and 7.3–25 μM, respectively. The effects induced by all five pH-sensitive compounds involve increased 5′-GMP binding, cellular accumulation, and DNA platination as well as stronger effects on DNA secondary structure at pH 6.0 than at pH 7.4. As exemplified by treatment of A549 cells with a 2-amino-4-methyl-1-pentanolato complex, induction of apoptosis is enhanced at pH 6.5. These results confirm the increased reactivity and in vitro activity of these compounds under slightly acidic conditions, encouraging further evaluation of ring-closed aminoalcoholatoplatinum(II) derivatives in solid tumors in vivo.


Anticancer drug Apoptosis Cellular accumulation DNA binding pH-sensitive prodrug 



Dulbecco’s modified Eagle’s medium


Fluorescence-activated cell sorting


Fifty percent growth inhibition


5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolcarbocyanine iodide


3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide


Poly(ADP-ribose) polymerase


Phosphate-buffered saline


Propidium iodide


Treated to control





This work was supported by the Austrian Research Promotion Agency (FFG, grant M811591; B.K.K.); and the Austrian Science Fund (FWF, grant L568; W.B.). Sara Daraei (St.-Marien-Hospital Lünen, Akademisches Lehrkrankenhaus der Westfälischen Wilhelms-Universität Münster) is gratefully acknowledged for assistance in writing parts of the manuscript.

Supplementary material

775_2012_970_MOESM1_ESM.pdf (88 kb)
Supplementary material 1 (PDF 88 kb)


  1. 1.
    Galanski M, Jakupec MA, Keppler BK (2005) Curr Med Chem 12:2075–2094PubMedCrossRefGoogle Scholar
  2. 2.
    Galanski M, Keppler BK (2007) Anticancer Agents Med Chem 7:55–73PubMedCrossRefGoogle Scholar
  3. 3.
    Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, Micksche M, Keppler B, Berger W (2008) Drug Resist Updates 11:1–16CrossRefGoogle Scholar
  4. 4.
    Gatenby RA, Gillies RJ (2004) Nat Rev Cancer 4:891–899PubMedCrossRefGoogle Scholar
  5. 5.
    Swietach P, Vaughan-Jones RD, Harris AL (2007) Cancer Metastasis Rev 26:299–310PubMedCrossRefGoogle Scholar
  6. 6.
    Stock C, Schwab A (2009) Pflugers Arch Eur J Physiol 458:981–992CrossRefGoogle Scholar
  7. 7.
    Tannock IF, Rotin D (1989) Cancer Res 49:4373–4384PubMedGoogle Scholar
  8. 8.
    Izumi H, Torigoe T, Ishiguchu H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (2003) Cancer Treat Rev 29:541–549PubMedCrossRefGoogle Scholar
  9. 9.
    Raghunand N, Martinez-Zaguilan R, Wright SH, Gillies RJ (1999) Biochem Pharmacol 57:1047–1058PubMedCrossRefGoogle Scholar
  10. 10.
    Kennedy KA, Rockwell S, Sartorelli AC (1980) Cancer Res 40:2356–2360PubMedGoogle Scholar
  11. 11.
    Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR (1990) Cancer Res 50:575–579PubMedGoogle Scholar
  12. 12.
    Siemann DW, Chapman M, Beikirch A (1991) Int J Radiat Oncol Biol Phys 20:287–289PubMedCrossRefGoogle Scholar
  13. 13.
    Skarsgard LD, Chaplin DJ, Wilson DJ, Skwarchuk MW, Vinczan A, Kristl J (1992) Int J Radiat Oncol Biol Phys 22:737–741PubMedCrossRefGoogle Scholar
  14. 14.
    Galanski M, Baumgartner C, Meelich K, Arion VB, Fremuth M, Jakupec MA, Schluga P, Hartinger CG, Keyserlingk N Graf v., Keppler BK (2004) Inorg Chim Acta 357:3237–3244Google Scholar
  15. 15.
    Galanski M, Baumgartner C, Arion V, Keppler BK (2003) Eur J Inorg Chem 14:2619–2625CrossRefGoogle Scholar
  16. 16.
    Aleksenko SS, Hartinger CG, Semenova O, Meelich K, Timerbaev AR, Keppler BK (2007) J Chromatogr A 1155:218–221PubMedCrossRefGoogle Scholar
  17. 17.
    Hartinger CG, Schluga P, Galanski M, Baumgartner C, Timerbaev AR, Keppler BK (2003) Electrophoresis 24:2038–2044PubMedCrossRefGoogle Scholar
  18. 18.
    Schluga P, Hartinger CG, Galanski M, Meelich K, Timerbaev AR, Keppler BK (2005) Analyst 130:1383–1389PubMedCrossRefGoogle Scholar
  19. 19.
    Zimmermann W, Galanski M, Keppler BK, Giester G (1999) Inorg Chim Acta 292:127–130CrossRefGoogle Scholar
  20. 20.
    Galanski M, Zimmermann W, Baumgartner C, Keppler BK (2001) Eur J Inorg Chem 5:1145–1149CrossRefGoogle Scholar
  21. 21.
    Dhara SC (1970) Indian J Chem 8:192–193Google Scholar
  22. 22.
    Kidani Y, Inagaki K, Iigo M, Hoshi A, Kuretani K (1978) J Med Chem 21:1315–1318PubMedCrossRefGoogle Scholar
  23. 23.
    Meelich K, Galanski M, Arion VB, Keppler BK (2006) Eur J Inorg Chem 12:2476–2483CrossRefGoogle Scholar
  24. 24.
    Mosmann T (1983) J Immunol Methods 65:55–63PubMedCrossRefGoogle Scholar
  25. 25.
    Grguric-Sipka S, Kowol CR, Valiahdi SM, Eichinger R, Jakupec MA, Roller A, Shova S, Arion VB, Keppler BK (2007) Eur J Inorg Chem 2007:2870–2878CrossRefGoogle Scholar
  26. 26.
    Egger AE, Rappel C, Jakupec MA, Hartinger CG, Heffeter P, Keppler BK (2009) J Anal At Spectrom 24:51–61PubMedCrossRefGoogle Scholar
  27. 27.
    Zorbas-Seifried S, Hartinger C, Meelich K, Galanski M, Keppler BK, Zorbas H (2006) Biochemistry 45:14817–14825PubMedCrossRefGoogle Scholar
  28. 28.
    Heffeter P, Jakupec MA, Körner W, Chiba P, Pirker C, Dornetshuber R, Elbling L, Sutterlüty H, Micksche M, Keppler BK, Berger W (2007) Biochem Pharmacol 73:1873–1886PubMedCrossRefGoogle Scholar
  29. 29.
    Laurencot CM, Kennedy KA (1995) Oncol Res 7:371–379PubMedGoogle Scholar
  30. 30.
    Stewart DJ (2007) Crit Rev Oncol Hematol 63:12–31PubMedCrossRefGoogle Scholar
  31. 31.
    Schwerdt G, Freudinger R, Schuster C, Weber F, Thews O, Gekle M (2005) Toxicol Sci 85:735–742PubMedCrossRefGoogle Scholar
  32. 32.
    Murakami T, Shibuya I, Ise T, Chen ZS, Akiyama SI, Nakagawa M, Izumi H, Nakamura T, Matsuo KI, Yamada Y, Kohno K (2001) Int J Cancer 93:869–874PubMedCrossRefGoogle Scholar
  33. 33.
    Berners-Price SJ, Appleton TG (2000) In: Kelland LR, Farrell NP (eds) Platinum-based drugs in cancer therapy. Humana, Totowa, pp 3–35CrossRefGoogle Scholar
  34. 34.
    Todd RC, Lovejoy KS, Lippard SJ (2007) J Am Chem Soc 129:6370–6371PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2013

Authors and Affiliations

  • Seied Mojtaba Valiahdi
    • 1
  • Alexander E. Egger
    • 1
  • Walter Miklos
    • 2
    • 4
  • Ute Jungwirth
    • 2
    • 4
  • Kristof Meelich
    • 1
  • Petra Nock
    • 1
  • Walter Berger
    • 2
    • 4
  • Christian G. Hartinger
    • 1
    • 3
  • Markus Galanski
    • 1
    • 3
  • Michael A. Jakupec
    • 1
    • 3
  • Bernhard K. Keppler
    • 1
    • 3
  1. 1.Institute of Inorganic ChemistryUniversity of ViennaViennaAustria
  2. 2.Institute of Cancer Research, Department of Medicine I and Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  3. 3.Research Platform “Translational Cancer Therapy Research”University of ViennaViennaAustria
  4. 4.Research Platform “Translational Cancer Therapy Research”Medical University of ViennaViennaAustria

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