Article Title

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

Authors

Svitlana Prylutska, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
Rostyslav Panchuk, Institute of Cell Biology, NAS of Ukraine, 14-16 Drahomanov Str., 79005 Lviv, Ukraine
Grzegorz Gouński, Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology UG-MUG, Abrahama 58, 80-307 Gdańsk, Poland
Larysa Skivka, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
Yuriy Prylutskyy, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
Vasyl Hurmach, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
Nadya Skorohyd, Institute of Cell Biology, NAS of Ukraine, 14-16 Drahomanov Str., 79005 Lviv, Ukraine
Agnieszka Borowik, Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology UG-MUG, Abrahama 58, 80-307 Gdańsk, Poland
Anna Woziwodzka, Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology UG-MUG, Abrahama 58, 80-307 Gdańsk, Poland
Jacek Piosik, Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology UG-MUG, Abrahama 58, 80-307 Gdańsk, Poland
Olena Kyzyma, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine Joint Institute for Nuclear Research, 6 Joliot-Curie Str., 141980 Dubna, Moscow reg., Russia
Vasil Garamus, Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, 1 Max-Planck Str., 21502 Geesthacht, Germany
Leonid Bulavin, Taras Shevchenko National University of Kyiv, 64 Volodymyrska Str., 01601 Kyiv, Ukraine
Maxim Evstigneev, Belgorod State University, 85 Pobedy Str., 308015 Belgorod, Russia
Anatoly Buchelnikov, Belgorod State University, 85 Pobedy Str., 308015 Belgorod, Russia
Rostyslav Stoika, Institute of Cell Biology, NAS of Ukraine, 14-16 Drahomanov Str., 79005 Lviv, Ukraine
Walter Berger, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, 1090, 8A Borschkegasse, Vienna, Austria
Uwe Ritter, Technical University of Ilmenau, Institute of Chemistry and Biotechnology, 25 Weimarer Str., 98693 Ilmenau, Germany
Peter Scharff, Technical University of Ilmenau, Institute of Chemistry and Biotechnology, 25 Weimarer Str., 98693 Ilmenau, Germany

Keywords

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

Abstract

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.

Graphical Abstract

DOI

https://doi.org/10.1007/s12274-016-1324-2

Publisher

Tsinghua University Press

Recommended Citation

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