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

• DOI: 10.1007/s12274-016-1324-2
• Publication Date: 2016-12-24T07:12:32Z
• Authors: 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
• Keywords: 0303 health sciences; 03 medical and health sciences; mutagenic activity; small-angle X-ray scattering; apoptosis; Lewis lung carcinoma (LLC); cytotoxicity; molecular docking; 3. Good health

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin (Cis) with C 60 fullerene (C 60 +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 C 60 +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 C 60 +Cis complex increases tumor growth inhibition, when compared to Cis or C 60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C 60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein (P-gp), multidrug resist ance 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 C 60 +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 o f secondary neoplasm formation. In conclusion, the C 60 +Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo , overcoming drug resistance likely by the potential of the C 60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C 60 +Cis complex might be a potential novel chemotherapy modification.