A proposed mechanism for the inhibitory effect of the anticancer agent titanocene dichloride on tumour gelatinases and other proteolytic enzymes

Abstract

Titanocene dichloride, the most studied metallocene, exhibits antiproliferative activity in a wide spectrum of murine and human tumours. In this article it is demonstrated that titanocene dichloride inhibits tumour gelatinases in a dose-dependent manner. Substrate saturation experiments and the fact that the IC(50) values were increased in correlation with collagen substrate concentrations indicate that the titanocene dichloride induced inhibition is of a competitive type. Titanocene dichloride also specifically inhibits clostridium collagenase and trypsin, particularly when collagens are used as substrates. Binding experiments demonstrate that cyclopentadiene-Ti(IV) moieties, resulting from titanocene dichloride at physiological pH, are bound mainly to different types of collagens and to a lesser extent to casein or bovine serum albumin, forming soluble and stable adducts. These results indicate that titanocene dichloride behaves as a competitive inhibitor against various proteolytic enzymes by binding to the substrate rather than to the enzyme active site. This property may be responsible for the antiangiogenic effect of titanocene dichloride and additionally contributes to its anticancer action.

Enantiopure titanocene complexes – direct evidence for paraptosis in cancer cells

“…However, experiments have indicated alternative mechanisms of action and cell death following detection of ligand-bound Ti(IV) complexes to other proteins (e.g. albumin) or proteolytic enzymes 13,14 . Recently described has been the potent and selective anticancer activity of organometallic-titanocene compounds, but lack of interaction between compounds and plasmid DNA implicated alternative biomolecular targets; accordingly, AKT and MAP kinase family protein kinase activity was inhibited 15 .…”

Water-soluble molybdenocene complexes with both proliferative and antiproliferative effects on cancer cell lines and their binding interactions with human serum albumin

“…This suggests that molybdenocene dichloride has more affinity for HSA than Cp 2 Mo(malonate) and [Cp 2 Mo(maltolato)]Cl, following the same pattern observed using the oxidation potentials, but we believe that these numbers are more realistic since they show that HSA–molybdenocene interaction could be significant. In fact, there are recent reports with evidence that HSA could be responsible for the transport and delivery of titanocene dichloride into the target place [54, 55]. …”

Cytotoxicity of a Ti(IV) compound is independent of serum proteins

“…SA has been shown to bind hard metals such as Ti(IV) in metal-chelate form (13,20). Binding to SA affords a mechanism by which a Ti(IV) compound, such as the titanocene moiety (22,23), could be delivered intact to cancer cells and directly exhibit its effect. Several hydrolysis-prone Ti(IV) compounds, including the titanocene moiety, importantly, bind to SA (13,20,22,23).…”

“…Binding to SA affords a mechanism by which a Ti(IV) compound, such as the titanocene moiety (22,23), could be delivered intact to cancer cells and directly exhibit its effect. Several hydrolysis-prone Ti(IV) compounds, including the titanocene moiety, importantly, bind to SA (13,20,22,23). However, similar to results with Tf, the addition of SA to cell-viability assays does not improve the cytotoxicity displayed by different Ti(IV) compounds (24), except Titanocene Y (24).…”