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

Nano Research 2017年第2期10卷 652-671页

作者： Svitlana Prylutska rostyslav.panchuk Grzegorz Golunski 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 Taras Shevchenko National University of Kyiv 64 Volodymyrska Str. 01601 Kyiv Ukraine Institute of Cell Biology NAS of Ukraine 14-16 Drahomanov 5tr. 79005 Lviv Ukraine Laboratory of Biophysics Intercollegiate Faculty ofBiotechnology UG-MUG Abrahama 58 80-307 Gdansk Poland Joint Institute for Nuclear Research 6 Joliot-Curie Str. 141980 Dubna Moscow reg. Russia Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research 1 Max-Planck Str. 21502 Geesthacht Germany Belgorod State University 85 Pobedy Str. 308015 Belgorod Russia Institute of Cancer Research and Comprehensive Cancer Center Medical University Vienna 1090 8A Borschkegasse Vienna Austria Institute of Chemistry and Biotechnology Technical University ofllmenau 25 Weimarer Str. 98693 Ilmenau Germany

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.

关键词： molecular docking,small-angle X-ray scattering,apoptosis,mutagenic activity lung carcinoma (LLC),cytotoxicity

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