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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

Abstract

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.

Keywords

Anticancer drug Apoptosis Cellular accumulation DNA binding pH-sensitive prodrug 

Abbreviations

DMEM

Dulbecco’s modified Eagle’s medium

FACS

Fluorescence-activated cell sorting

GI50

Fifty percent growth inhibition

JC-1

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

MTT

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

PARP

Poly(ADP-ribose) polymerase

PBS

Phosphate-buffered saline

PI

Propidium iodide

T/C

Treated to control

Tris

Tris(hydroxymethyl)aminomethane

Notes

Acknowledgments

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)

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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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