C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance
molecular docking, small-angle X-ray scattering, apoptosis, mutagenic activity, Lewis lung carcinoma (LLC), cytotoxicity
ABSTRACT 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 chemotherapyresistant 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.
Tsinghua University Press
Svitlana Prylutska,Rostyslav Panchuk,Grzegorz Gołuński,Larysa Skivka,Yuriy Prylutskyy,Vasyl Hurmach,Nadya Skorohyd,Agnieszka Borowik,Anna Woziwodzka,Jacek Piosik,Olena Kyzyma,Vasil Garamus,Leonid Bulavin,Maxim Evstigneev,Anatoly Buchelnikov,Rostyslav Stoika,Walter Berger,Uwe Ritter,Peter Scharff, C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance. NanoRes.2017, 10(2): 652–671