Session Speaker

The New Platinum Compound Cis-Dichloro(2-{11-[(tetrahydro-2H-pyran-2-yl)oxy]undecyl}propan-1,3-diamino)platin(II) Overcomes CDDP Resistance and Induces a DNA-Independent and Caspase-Independent Apoptotic Cell Death in Testicular Cancer
A. Dietrich, T. Mueller, R. Paschke, F. Reipsch, A. Fruehauf, H.-J. Schmoll and W. Voigt
Germany

Resistance to platinum based chemotherapy in advanced testicular cancer (TC) determines the outcome of the mainly younger patients. Thus, the development of non cross-resistant platinum compounds is essential to improve the curative potential of chemotherapy.

The new cisplatinum conjugate cis-Dichloro(2-{11-[(tetrahydro-2H-pyran-2-yl)oxy]undecyl}propan-1,3-diamino)platin(II) (THP-12) developed by our group completely overcame intrinsic resistance of TC cell lines. In comparison to cisplatin, THP12 induced accelerated DNA-fragmentation, release of cytochrome C and cleavage of caspase 3 and PARP. Notably, despite higher and faster cellular platinum uptake, the rate of THP-12 recovery at the DNA-level was clearly lower as compared to cisplatin. In contrast to cisplatin, no upregulation of p53 protein or induction of cell cycle arrest was observed. Interestingly, although THP-12 and cisplatin both induced caspase-3 and PARP cleavage as well as the morphological features of apoptosis, only in the case of cisplatin the induction of apoptosis could be blocked by co treatment with a PAN caspase inhibitor. THP-12, in contrast to cisplatin, significantly released intracellular calcium, lead to the formation of reactive oxygen species and loss of mitochondrial transmembrane potential.

In conclusion, THP-12 overcomes cisplatin resistance in TC and appears to induce apoptosis through different initial pathways as compared to cisplatin.