A proposed mechanism for the inhibitory effect of the anticancer agent titanocene dichloride on tumour gelatinases and other proteolytic enzymes.
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.
Pavlaki
Maria
M
Department of Chemistry, School of Natural Sciences, University of Patras, Patras, Greece.
Debeli
Katerina
K
Triantaphyllidou
Irene-Eva
IE
Klouras
Nikolaos
N
Giannopoulou
Eleftheria
E
Aletras
Alexios J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001485:Basement Membrane / Q000201:enzymology; D020134:Catalytic Domain; D002417:Cattle; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000201:enzymology*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D005780:Gelatin; D003094:Collagen; D018093:Gelatinases; C020528:titanocene dichloride