C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin （Cis） with C60 fullerene （C60＋Cis complex） and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy- resistant human leukemia cell sublines （resistant to Adriamycin and Vinculin, respectively）. We discovered that the action of the C60＋Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma （LLC） C57BL/6J male mice showed that the C60＋Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein （P-gp）, multidrug resistance protein 1 （MRP-1）, and multidrug resistance protein 2 （MRP-2） molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60＋Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60＋Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60＋Cis complex might be a potential novel chemotherapy modification.