Franskevych D. Biochemical mechanisms of cisplatin and fullerene C60 combined effect on normal and malignant cells

Cisplatin - induced toxic effect against erythrocytes and thymocytes was inhibited when cells were preincubated with fullerene C60. Thus, cytoprotective properties of fullerene C60 in normal cells was shown. With the use of fluorescent-labeled C60 obtained by covalent conjugation of C60 with rhodamine В-isothiocyanate (C60-RITC) the accumulation of nanostructure in leukemic L1210 cells was demonstrated. Phototoxic effect of fullerene C60 was detected when leukemic cells were incubated with fullerene C60 and irradiated by visible light. Phototoxic effect of fullerene C60 was realized not only against sensitive, but against resistant to cisplatin leukemic cells as well. Combined treatment with photoexcited C60 and 1mkg/ml cisplatin allowed to intensify cytotoxic effect on both sensitive and resistant to cisplatin leukemic cells compared to effects of agents used alone. The decrease of L1210 and L1210R cells viability after combined treatment with photoexcited C60 and cisplatin was shown to be associated with cells arrest in apoptotic SubG1 phase of cell cycle. Intensification of ROS generation, activation of redox-sensitive p38 kinase, elevation of free cytosolic Ca2+ concentration ([Ca2+]i) and capacitive Ca2+ entry, dissipation of mitochondrial membrane potential were determined as early cytotoxic effects of combined treatment with photoexcited fullerene C60 and cisplatin. The data obtained indicate that combination of photoexcited fullerene C60 with cisplatin allows to increase cytotoxicity against leukemic L1210 cells and to restore sensibility of L1210 resistant cells to cisplatin by enhancing extranuclear proapoptotic effects of the drug.