A cycloplatinated compound of p-isopropylbenzaldehyde thiosemicarbazone and its chloro-bridged derivative induce apoptosis in cis-DDP resistant cells which overexpress the H-ras oncogene.

Abstract cis -Diamminedichloroplatinum(II) ( cis -DDP) is a widely used antitumour drug which produces important damage on the DNA inducing apoptosis in several cell lines. We have analysed the cytotoxic activity of novel cyclometallated complexes of p -isopropylbenzaldehyde thiosemicarbazone ( p -is.TSCN) and their dimeric chloro-bridged derivatives in murine keratinocytes transformed by the H- ras oncogene which are resistant to cis -DDP (Pam- ras cells). The data show that, in contrast with cis -DDP, the tetrameric cycloplatinated complex [Pt( p -is.TSCN)] 4 and its dimeric chloro-bridged derivative [Pt(μCl)( p -is.TSCN)] 2 have a good in vitro therapeutic index when comparing the cytotoxicity in Pam- ras cells to normal murine keratinocytes (Pam 212 cells) since they induce cell death in Pam- ras cells at drug concentrations significantly lower than those needed to kill Pam 212 cells. At equitoxic doses (IC 90 ), both complexes produce characteristic features of apoptosis in Pam- ras cells together with a drastic decrease in levels of H- ras protein. These effects are not observed when the cells are treated with the IC 90 of the cis -DDP drug nor the p -is.TSCN ligand. Altogether, these results suggest that the platinum compounds [Pt( p -is.TSCN)] 4 and [Pt(μCl)( p -is.TSCN)] 2 might have potential as antitumour agents in view of their specific induction of apoptosis in cis -DDP resistant cells.