Abstract
Purpose
The ruthenium complex salt indazolium trans-[tetrachlorobisindazole-ruthenate(III)] (KP1019) and the analogous sodium salt KP1339 are effective tumor-inhibiting drugs in experimental therapy of autochthonous colorectal carcinomas in rats. This paper examines the cell biological mechanisms underlying their antineoplastic effects.
Methods
Colorectal tumor cell lines were used to analyze uptake of the ruthenium(III) complexes into the cells and the mechanism as well as the efficacy of their cytotoxic effects.
Results
KP1019 and KP1339 are efficiently taken up into the cells: 100 µM ruthenium(III) complex in the growth medium led to the uptake of 120–160 ng ruthenium per 106 cells within 30 min. Uptake of KP418 was tenfold lower correlating with its lower cytotoxic efficiency. KP1019 and KP1339 induced apoptosis in SW480 and HT29 cells predominantly by the intrinsic mitochondrial pathway as indicated by loss of mitochondrial membrane potential. Correspondingly sensitivity of the cells paralleled expression of bcl2 while it was only slightly affected by mutations in Ki-ras.
Conclusions
Our data demonstrate that trans-[tetrachlorobisindazole-ruthenate(III)] complex salts are promising candidate drugs in the second-line treatment of colorectal cancers resistant to other cytostatic drugs and has been introduced into phase I clinical trials.
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Abbreviations
- 5-FU:
-
5-fluorouracil
- MEM:
-
Minimal essential medium
- FCS:
-
Fetal calf serum
- PBS:
-
Phosphate-buffered saline
- HBSS:
-
Hank’s balanced salt solution
- TMAH:
-
Tetramethylammoniumhydroxide
- LDH:
-
Lactatedehydrogenase
- MMP:
-
Mitochondrial membrane potential
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Kapitza, S., Pongratz, M., Jakupec, M.A. et al. Heterocyclic complexes of ruthenium(III) induce apoptosis in colorectal carcinoma cells. J Cancer Res Clin Oncol 131, 101–110 (2005). https://doi.org/10.1007/s00432-004-0617-0
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DOI: https://doi.org/10.1007/s00432-004-0617-0