Antitumoral Activity of 3rd Generation Derivative Lobaplatin in In Vitro Models of Triple-Negative Breast Cancers.

Abstract

Abstract Introduction:Triple-negative breast cancers are characterized by aggressive growth and early metastasic spread. Some preliminary clinical data have demonstrated good anti-tumor activity of platinum derivatives. 3rd generation compound Lobaplatin* has shown a favorable toxicity profile as compared to Cisplatin. We therefore evaluated this compound in in vitro models of triple negative breast cancers.Study design:Triple-negative humane breast cancer cell lines HCC 1937 and HCC 1806 were treated with increasing concentrations of Lobaplatin and Cisplatin (0,16-10 μm). Cells were incubated for 24, 48 and 72 h with both substances in serum-free and serum-containing medium, in order to evaluate cytotoxic effects in proliferating as well as in metabolically inactive cells. Induction of apoptosis was tested by cleavage of PARP and Caspase 3 as demonstrated by western blot analysis. Subsequently cells were coincubated with Lobaplatin and multi-caspase inhibitor ZVAD-fmk, in order to check if cell death induced by Lobaplatin can be abrogated by inhibition of classical apoptosis. Cytotoxic effects were evaluated by crystal-violet assay. To investigate in which phase of the cell cycle cytotoxicity is most pronounced, cell cycle FACS analysis was performed after treatment with various concentrations of Lobaplatin.Results:Lobaplatin showed a somewhat better anti-tumor activity in both cell lines than Cisplatin. Lobaplatin Induced cleavage of PARP and procaspase 3 indicative for induction of classical apoptosis. However, cytotoxic effects of Lobaplatin were not decreased by multi-caspase inhibitor ZVAD-fmk. Cell-cycle FACS analysis showed, that sub-G0/1 fraction (indicactive for apoptotic/necrotic cells) was increased and G2 fraction was decreased dose-dependently by treatment with Lobaplatin.Conclusion:Lobaplatin showed a good anti-tumor activity in in vitro models of triple negative breast cancers which was at least equal to Cisplatin. Main mechanism of ytotoxicity was programmed cell death, which could not be abrogated by multi-caspase inhibition. Due to the good anti-tumor activity and the favorable toxicity profile, Lobaplatin should be considered for clinical studies in triple negative breast cancers.*Aeterna/Zentaris GmbH, Frankfurt/M Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6115.