Metal Containing Cytostatics and Their Interaction with Cellular Thiol Compounds Causing Chemoresistance
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 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.