Kuznietsova H. Influence of growth factors receptors nonspecific inhibitors on the inflammation-fibrosis-carcinogenesis axis (on the example of digestive organs)

The possibility and suitability of nonspecific growth factor receptor inhibitors impact on colonic and liver inflammation, fibrogenesis and carcinogenesis as successive links of one pathological process using C60 fullerenes and pyrrole derivatives 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione (MI- 1) and 3-{[4-chloro-1-(4-chlorobenzyl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl] amino}phenyl 4-[6,6]-phenyl-C61-butanoate (C60-MI-3OH) as the examples was investigated. Pyrrole derivatives and C60FAS suppressed rat colon and liver acute and chronic inflammation, while the anti-inflammatory and protective effects of the compounds are more pronounced under chronic pathology. Test compounds could inhibit the initial stages of liver fibrous degeneration (acute and chronic cholangitis) and reduce its local and systemic manifestations. The ability of C60FAS to inhibit liver fibrosis and cirrhosis and subsequent hepatocellular carcinoma development and to improve animal survival was demonstrated. However, under similar biliary pathologies C60FAS therapeutic effect was less pronounced. MI-1, C60FAS and C60-MI-3OH decreased the number of colorectal tumors (by 34-64%) and total tumor lesions area (by 54-72%) under colon cancer, and contributed to the reduction of its negative systemic manifestations as well. C60FAS, MI-1 and C60-MI-3OH could form stable bonds with the ATP-binding sites of the growth factor receptors EGFR and FGFR, and EGFR and VEGFR, respectively, indicating their ability to block those. The mechanisms of tested compounds’ biological activity other than growth factor receptors inhibition included antiproliferative and proapoptotic action, impact on cytoskeletal proteins and p53 expression and target organs’ redox balance. Hence, growth factor receptors non-specific inhibitors (like pyrrole derivatives and C60 fullerenes) could be considered as universal tools of influencing the inflammation, fibrosis and carcinogenesis as successive links of one pathological process.