Synthesis, characterization and DNA modification induced by a novel Pt(IV)-bis(monoglutarate) complex which induces apoptosis in glioma cells

Programmed cell death or apoptosis is a mechanism for the elimination of cells that occurs not only in physiological processes but also in drug-induced tumor cell death. Thus, because cisplatin, cis-diamminechloroplatinum (II), produces important damages on the DNA inducing apoptosis in several cell lines it has become a widely used antitumor drug. However, cisplatin possesses some dose-limiting toxicities mainly nephrotoxicity. Pt(IV) complexes, such as iproplatin, ormaplatin, and JM216 are a new class of platinum complexes that exhibits less toxicity than cisplatin. Some of these complexes have shown significant antitumor activity and a low cross-resistance to cisplatin. In the present paper, we have analyzed the DNA binding mode and the cytotoxicity of a novel Pt(IV)-bis (monoglutarate) complex. The data show that this novel complex produces DNA interstrand cross-links to a higher extent and with a faster kinetics than cisplatin. Also the Pt(IV)-bis (monoglutarate) complex kills glioma cells at drug concentrations significantly lower than those of cisplatin. Interestingly, this Pt(IV) complex produces in the glioma cells characteristic features of apoptosis such as 'DNA laddering' and fragmented nuclei. Moreover, the p53 protein accumulates early in glioma cells as a result of Pt(IV)-bis (monoglutarate) treatment. These data indicate that the Pt(IV)-bis (monoglutarate) complex induces apoptosis in glioma cells through a p53-dependent pathway.