Cancer Wars: Significance of Protein Unfolding in Cancer and Its Inhibition with Natural Amphiphilic Substances

It is essential to bear in mind that the native conformation of human proteins is stabilized by intra-molecular disulfide (S–S) bonds between a single or multiple polypeptide chains. The formation of S–S bonds is catalyzed by protein disulfide isomerase (PDI) (1), the activation of which is associated with a number of human diseases, such as myocardial infarction, stroke, and cancer. Unless proper chaperone proteins are available the accidental cleavage of S–S linkages will result in the unfolding and scrambled refolding of the polypeptide chains thus producing non-native species present in many degenerative diseases (2– 5). This process is the most common protein post-translational modification that, for example, in a protein with 9 disulfide bridges can theoretically form 34,459,425 different disulfide-bonded isomers, only one with a correct protein function. However, the most damaging consequence of such a modification is the formation of protein aggregates known as “inclusion bodies” that are resistant to the enzymatic degradation (6). This unusual phenomenon is the result of the formation of intermolecular hydrophobic bonds, which in contrast to peptide links are not susceptible to the catalytic hydrolysis. It is known that the strongest and practically irreversible protein interactions involve hydrophobic bonds, which in native proteins are buried inside their tertiary structure (7). One of the blood proteins rich in disulfides is fibrinogen (Fbg), the physiologic function of which is to provide hemostatic fibrin plug formed by the action of enzyme thrombin. This insoluble polymer, when formed at the site of vessel wall injury, is eventually removed by the action of fibrinolytic enzyme system, to give space for the growth of a connective tissue and to ensure proper wound healing. To speed up the process of fibrin elimination from the coronary or cerebral circulations, several thrombolytic therapies have been devised with the use of a variety of fibrinolytic agents. It is, however, well recognized in clinical practice that such therapies are effective only when installed 3–5 h after the onset of thrombosis (8). This enigma is now resolved by the discovery of the alternative pathway of blood coagulation induced with iron (9). Thus, in contrast to thrombingenerated fibrin the iron-induced parafibrin is totally resistant to the fibrinolytic degradation. This is due to the fact that parafibrin has different a tertiary structure than fibrin formed with thrombin. We have showed that such a dramatic modification of fibrin structure is due to the unfolding and scrambled refolding of Fbg disulfidelinked subunits leading to the exposure of hydrophobic epitopes in their polypeptide chains (9). The cleavage of disulfide bonds is induced by biologically highly reactive hydroxyl radicals (HO) formed in the reaction between trivalent iron with hydroxyl groups of water according to the following formula: