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

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 

机构地区：[1]Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine [2]Institute of Cell Biology, NAS of Ukraine, 14-16 Drahomanov 5tr., 79005 Lviv, Ukraine [3]Laboratory of Biophysics, Intercollegiate Faculty ofBiotechnology UG-MUG, Abrahama 58, 80-307 Gdansk, Poland [4]Joint Institute for Nuclear Research, 6 Joliot-Curie Str., 141980 Dubna, Moscow reg., Russia [5]Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, 1 Max-Planck Str., 21502 Geesthacht, Germany [6]Belgorod State University, 85 Pobedy Str., 308015 Belgorod, Russia [7]Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, 1090, 8A Borschkegasse, Vienna, Austria [8]Institute of Chemistry and Biotechnology, Technical University ofllmenau, 25 Weimarer Str., 98693 Ilmenau, Germany

出　　处：《Nano Research》2017年第2期652-671,共20页纳米研究（英文版）

摘　　要：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.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 

分 类 号：O[理学]