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.
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 analyzed 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(microCl)(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 (IC90), 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 IC90 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(microCl)(p-is.TSCN)]2 might have potential as antitumour agents in view of their specific induction of apoptosis in cis-DDP resistant cells.
Pérez
J M
JM
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Spain.
Quiroga
A G
AG
Montero
E I
EI
Alonso
C
C
Navarro-Ranninger
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D019281:Dimerization; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D011905:Genes, ras; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D013882:Thiosemicarbazones
D000970:Antineoplastic Agents; D013882:Thiosemicarbazones; C111909:4-isopropylbenzaldehyde thiosemicarbazone; D002945:Cisplatin