Molecular genotoxicity profiles of apoptosis-inducing vanadocene complexes

Metallocene complexes containing vanadium induce apoptosis in human cancer cells by an as yet unknown mechanism and may therefore be useful as a new c lass of cytotoxic anticancer drugs. Ultrastructural studies showing the for mation of metallocene-DNA complexes prompted the hypothesis that their mech anism of action may resemble the DNA damage induced by cisplatin, Molecular genotoxicity testing provides insights into the mechanisms of action of ne w chemotherapeutic agents. Therefore, we determined the effects of three cy totoxic vanadocene complexes, vanadocene dichloride, vanadocene dithiocyana te, and vanadocene dioxycyanate, an genomic stability using the yeast DEL r ecombination assay and transcriptional activation of genotoxic stress-speci fic promoters in human HepG2 cells using the CAT-Tox(L) assay. Cisplatin ca used an 11-fold increase of recombination frequency in yeast and induced tr anscriptional activation of the DNA damage-associated promoters such as the minimum promoter containing p53 response elements and the GADD45 promoter in addition to activating the promoters for c-fos, heat shack protein 70, m etallothionine IIa, and the minimum promoter containing nuclear factor kapp a(kappa)B response elements. In contrast to cisplatin, vanadocene complexes did not increase the DEL recombination frequency in yeast nor did they act ivate any of the DNA damage-associated promoters in HepG2 cells. Vanadocene complexes triggered activation of the c-fos promoter without affecting the minimum promoter containing p53 response elements or the GADD45 promoter. These results indicate that the apoptotic signal of vanadocene complexes is not triggered by primary DNA damage and it does not require p53 induction, thereby disproving the hypothesis that it mechanistically resembles the cy totoxic action of cisplatin. (C) 1999 Academic Press.