Title:Metal Containing Cytostatics and Their Interaction with Cellular Thiol Compounds Causing Chemoresistance
Volume: 16
Issue: 6
Author(s): Jan Hrabeta, Vojtech Adam, Tomas Eckschlager, Eva Frei, Marie Stiborova and Rene Kizek
Affiliation:
Keywords:
Metal-containing cytostatic drugs, platinum, resistance, chemoresistance, glutathione, metallothioneins.
Abstract: The history of metal based cytostatics began in the 1970s by discovering the effects of cisplatin. Since
then several generations of platinum based cytostatics have started to be the key weapon against tumor development and metastasis
occurrence. Nevertheless, some attention has been also paid to non-platinum metals, such as ruthenium, titanium, gallium, iron, cobalt,
gold, and palladium. Ruthenium, titanium, and gallium complexes have been also tested in clinical studies. This boom in metal based
cytostatics can be explained by great effort paid to the elucidation of mechanisms of tumor resistance to these drugs. The known
mechanisms of drug resistance are: (i) down regulation, over-expression, or modification of molecules of interest; (ii) increased drug
efflux; (iii) induction of anti-apoptotic mechanisms or inactivation of pro-apoptotic mechanisms; (iv) changes in enzymes with an ability
to activate or detoxify a drug; (v) low access of the drug to a tumor; and/or (vi) alteration in drug metabolism or excretion [1]. Often
discussed but not largely reviewed and summarized is the intracellular inactivation of platinum drugs by coordination to thiol containing
biomolecules glutathione (GSH) and metallothioneins (MTs). Overexpression of MT and/or GSH may cause resistance to anticancer
drugs. Thus, greater attention should be paid to these interactions in case to overcome the resistance of tumor to cytostatics.
