Influence of extracellular pH on the cytotoxicity, cellular accumulation, and DNA interaction of novel pH-sensitive 2-aminoalcoholatoplatinum(II) complexes.
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-κ(2)N,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.
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Seied Mojtaba
SM
Valiahdi
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Alexander E
AE
Egger
Institute of Cancer Research, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
Walter
W
Miklos
Institute of Cancer Research, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
Ute
U
Jungwirth
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Kristof
K
Meelich
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Petra
P
Nock
Institute of Cancer Research, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
Walter
W
Berger
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Christian G
CG
Hartinger
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Mathea Sophia
MS
Galanski
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
Michael A
MA
Jakupec
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria. bernhard.keppler@univie.ac.at.|Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria. bernhard.keppler@univie.ac.at.
Bernhard K
BK
Keppler
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D016213:Cyclins / Q000378:metabolism; D004270:DNA, Circular / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry; D004355:Drug Stability; D006157:Guanosine Monophosphate / Q000737:chemistry; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010957:Plasmids / Q000737:chemistry; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D016213:Cyclins; D004270:DNA, Circular; D004278:DNA, Superhelical; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006157:Guanosine Monophosphate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin