Nano Research

, Volume 10, Issue 2, pp 652–671 | Cite as

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

  • Svitlana Prylutska
  • Rostyslav Panchuk
  • Grzegorz Gołuński
  • Larysa Skivka
  • Yuriy PrylutskyyEmail author
  • Vasyl Hurmach
  • Nadya Skorohyd
  • Agnieszka Borowik
  • Anna Woziwodzka
  • Jacek PiosikEmail author
  • Olena Kyzyma
  • Vasil Garamus
  • Leonid Bulavin
  • Maxim EvstigneevEmail author
  • Anatoly Buchelnikov
  • Rostyslav Stoika
  • Walter Berger
  • Uwe Ritter
  • Peter Scharff
Research Article


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.


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


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



We gratefully acknowledge the technical support from Clement Blanchet (EMBL) at the P12 BioSAXS beamline (EMBL/DESY, PETRA III). The research was partially supported by Russian Science Fund (No. 14-14-00328). S. Prylutska receives financial support by the Academician Platon Kostyuk Foundation, R. Panchuk receives financial support by West-Ukrainian BioMedical Research Center (WUMBRC) and by grant of Nationl Academy of Sciences of Ukraine for young scientists.

Supplementary material

12274_2016_1324_MOESM1_ESM.pdf (651 kb)
C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance


  1. [1]
    Corrie, P. G. Cytotoxic chemotherapy: Clinical aspects. Medicine 2008, 36, 24–28.CrossRefGoogle Scholar
  2. [2]
    de Vita, V. T.; Hellman, S.; Rosenberg, S. A. Principles and Practice of Oncology; 6th ed.; Lippincott, Williams & Wilkins: Philadelphia, 2001.Google Scholar
  3. [3]
    Hirsch, J. An anniversary for cancer chemotherapy. JAMA 2006, 296, 1518–1520.CrossRefGoogle Scholar
  4. [4]
    Florea, A. M.; Busselberg, D. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel) 2011, 3, 1351–1371.CrossRefGoogle Scholar
  5. [5]
    Huynh, V. T.; Scarano, W.; Stenzel, M. H. Drug delivery systems for platinum drugs. In Nanopharmaceutics. Liang, X. J., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2012; pp 201–241.CrossRefGoogle Scholar
  6. [6]
    Carmona, R.; Liang, X.-J. Improving platinum efficiency: Nanoformulations. In Nanopharmaceutics. Liang, X. J., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2012; pp 243–274.CrossRefGoogle Scholar
  7. [7]
    Liu, L.; Ye, Q.; Lu, M.; Lo, Y. C.; Hsu, Y. H.; Wei, M. C.; Chen, Y. H.; Lo, S. C.; Wang, S. J.; Bain, D. J. et al. A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs. Sci. Rep. 2015, 5, 10881.CrossRefGoogle Scholar
  8. [8]
    Dong, X. P.; Xiao, T. H.; Dong, H.; Jiang, N.; Zhao, X. G. Endostar combined with cisplatin inhibits tumor growth and lymphatic metastasis of Lewis lung carcinoma xenografts in mice. Asian Pac. J. Cancer Prev. 2013, 14, 3079–3083.CrossRefGoogle Scholar
  9. [9]
    Yu, H. Y.; Tang, Z. H.; Li, M. Q.; Song, W. T.; Zhang, D. W.; Zhang, Y.; Yang, Y.; Sun, H.; Deng, M. X.; Chen, X. S. Cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for potential cancer therapy: Preparation, in vitro and in vivo evaluation. J. Biomed. Nanotechnol. 2016, 12, 69–78.CrossRefGoogle Scholar
  10. [10]
    Cataldo, F.; Da Ros, T. Medicinal Chemistry and Pharmacological Potential of Fullerenes and Carbon Nanotubes; Springer: Amsterdam, 2008.Google Scholar
  11. [11]
    Andrievsky, G.; Klochkov, V.; Derevyanchenko, L. Is the C60 fullerene molecule toxic?! Fullerenes, Nanotubes, Carbon Nanostruct. 2005, 13, 363–376.CrossRefGoogle Scholar
  12. [12]
    Prylutska, S. V.; Matyshevska, O. P.; Golub, A. A.; Prylutskyy, Y. I.; Potebnya, G. P.; Ritter, U.; Scharff, P. Study of C60 fullerenes and C60-containing composites cytotoxicity in vitro. Mater. Sci. Eng. C 2007, 27, 1121–1124.CrossRefGoogle Scholar
  13. [13]
    Johnston, H. J.; Hutchinson, G. R.; Christensen, F. M.; Aschberger, K.; Stone, V. The biological mechanisms and physicochemical characteristics responsible for driving fullerene toxicity. Toxicol. Sci. 2010, 114, 162–182.CrossRefGoogle Scholar
  14. [14]
    Prylutska, S.; Bilyy, R.; Overchuk, M.; Bychko, A.; Andreichenko, K.; Stoika, R.; Rybalchenko, V.; Prylutskyy, Y.; Tsierkezos, N. G.; Ritter, U. Water-soluble pristine fullerenes C60 increase the specific conductivity and capacity of lipid model membrane and form the channels in cellular plasma membrane. J. Biomed. Nanotechnol. 2012, 8, 522–527.CrossRefGoogle Scholar
  15. [15]
    Bedrov, D.; Smith, G. D.; Davande, H.; Li, L. W. Passive transport of C60 fullerenes through a lipid membrane: A molecular dynamics simulation study. J. Phys. Chem. B 2008, 112, 2078–2084.CrossRefGoogle Scholar
  16. [16]
    Qiao, R.; Roberts, A. P.; Mount, A. S.; Klaine, S. J.; Ke, P. C. Translocation of C60 and its derivatives across a lipid bilayer. Nano Lett. 2007, 7, 614–619.CrossRefGoogle Scholar
  17. [17]
    Gharbi, N.; Pressac, M.; Hadchouel, M.; Szwarc, H.; Wilson, S. R.; Moussa, F. [60]fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. Nano Lett. 2005, 5, 2578–2585.CrossRefGoogle Scholar
  18. [18]
    Prylutska, S. V.; Grynyuk, I. I.; Matyshevska, O. P.; Prylutskyy, Y. I.; Ritter, U.; Scharff, P. Anti-oxidant properties of C60 fullerenes in vitro. Fullerenes, Nanotubes, Carbon Nanostruct. 2008, 16, 698–705.CrossRefGoogle Scholar
  19. [19]
    Prylutska, S. V.; Burlaka, A. P.; Klymenko, P. P.; Grynyuk, I. I.; Prylutskyy, Y. I.; Schü tze, C.; Ritter, U. Using water-soluble C60 fullerenes in anticancer therapy. Cancer Nanotechnol. 2011, 2, 105–110.CrossRefGoogle Scholar
  20. [20]
    Prylutska, S. V.; Burlaka, A. P.; Prylutskyy, Y. I.; Ritter, U.; Scharff, P. Pristine C(60) fullerenes inhibit the rate of tumor growth and metastasis. Exp. Oncol. 2011, 33, 162–164.Google Scholar
  21. [21]
    Chen, Z. Y.; Ma, L. J.; Liu, Y.; Chen, C. Y. Applications of functionalized fullerenes in tumor theranostics. Theranostics 2012, 2, 238–250.CrossRefGoogle Scholar
  22. [22]
    Didenko, G.; Prylutska, S.; Kichmarenko, Y.; Potebnya, G.; Prylutskyy, Y.; Slobodyanik, N.; Ritter, U.; Scharff, P. Evaluation of the antitumor immune response to C60 fullerene. Materialwiss. Werkstofftech. 2013, 44, 124–128.CrossRefGoogle Scholar
  23. [23]
    Kato, S.; Aoshima, H.; Saitoh, Y.; Miwa, N. Fullerene-C60 derivatives prevent UV-irradiation/TiO2-induced cytotoxicity on keratinocytes and 3D-skin tissues through antioxidant actions. J. Nanosci. Nanotechnol. 2014, 14, 3285–3291.CrossRefGoogle Scholar
  24. [24]
    Bozdaganyan, M. E.; Orekhov, P. S.; Shaytan, A. K.; Shaitan, K. V. Comparative computational study of interaction of C60-fullerene and tris-malonyl-C60-fullerene isomers with lipid bilayer: Relation to their antioxidant effect. PLoS One 2014, 9, e102487.CrossRefGoogle Scholar
  25. [25]
    Zhu, J. D.; Ji, Z. Q.; Wang, J.; Sun, R. H.; Zhang, X.; Gao, Y.; Sun, H. F.; Liu, Y. F.; Wang, Z.; Li, A. D. et al. Tumorinhibitory effect and immunomodulatory activity of fullerol C60(OH)x. Small 2008, 4, 1168–1175.CrossRefGoogle Scholar
  26. [26]
    Evstigneev, M. P.; Buchelnikov, A. S.; Voronin, D. P.; Rubin, Y. V.; Belous, L. F.; Prylutskyy, Y. I.; Ritter, U. Complexation of C60 fullerene with aromatic drugs. ChemPhysChem 2013, 14, 568–578.CrossRefGoogle Scholar
  27. [27]
    Prylutskyy, Y. I.; Evstigneev, M. P.; Pashkova, I. S.; Wyrzykowski, D.; Woziwodzka, A.; Golunski, G.; Piosik, J.; Cherepanov, V. V.; Ritter, U. Characterization of C60 fullerene complexation with antibiotic doxorubicin. Phys. Chem. Chem. Phys. 2014, 16, 23164–23172.CrossRefGoogle Scholar
  28. [28]
    Prylutska, S. V.; Didenko, G. V.; Potebnya, G. P.; Bogutska, K. I.; Prylutskyy, Y. I.; Ritter, U.; Scharff, P. Toxic effect of C60 fullerene-doxorubicin complex towards tumor and normal cells in vitro. Biopolym. Cell 2014, 30, 372–376.CrossRefGoogle Scholar
  29. [29]
    Panchuk, R. R.; Prylutska, S. V.; Chumak, V. V.; Skorokhyd, N. R.; Lehka, L. V.; Evstigneev, M. P.; Prylutskyy, Y. I.; Berger, W.; Heffter, P.; Scharff, P. et al. Application of C60 fullerene-doxorubicin complex for tumor cell treatment in vitro and in vivo. J. Biomed. Nanotechnol. 2015, 11, 1139–1152.CrossRefGoogle Scholar
  30. [30]
    Prylutska, S. V.; Skivka, L. M.; Didenko, G. V.; Prylutskyy, Y. I.; Evstigneev, M. P.; Potebnya, G. P.; Panchuk, R. R.; Stoika, R. S.; Ritter, U.; Scharff, P. Complex of C60 fullerene with doxorubicin as a promising agent in antitumor therapy. Nanoscale Res. Lett. 2015, 10, 499.CrossRefGoogle Scholar
  31. [31]
    Prylutskyy, Y. I.; Evstigneev, M. P.; Cherepanov, V. V.; Kyzyma, O. A.; Bulavin, L. A.; Davidenko, N. A.; Scharff, P. Structural organization of C60 fullerene, doxorubicin, and their complex in physiological solution as promising antitumor agents. J. Nanopart. Res. 2015, 17, 45.CrossRefGoogle Scholar
  32. [32]
    Prylutskyy, Y. I.; Cherepanov, V. V.; Evstigneev, M. P.; Kyzyma, O. A.; Petrenko, V. I.; Styopkin, V. I.; Bulavin, L. A.; Davidenko, N. A.; Wyrzykowski, D.; Woziwodzka, A. et al. Structural self-organization of C60 and cisplatin in physiological solution. Phys. Chem. Chem. Phys. 2015, 17, 26084–26092.CrossRefGoogle Scholar
  33. [33]
    Levi, J. A.; Aroney, R. S.; Dalley, D. N. Haemolytic anaemia after cisplatin treatment. BMJ 1981, 282, 2003–2004.CrossRefGoogle Scholar
  34. [34]
    Aguilar-Markulis, N. V.; Beckley, S.; Priore, R.; Mettlin, C. Auditory toxicity effects of long-term cisdichlorodiammineplatinum II therapy in genitourinary cancer patients. J. Surg. Oncol. 1981, 16, 111–123.CrossRefGoogle Scholar
  35. [35]
    Zhou, W. J.; Kavelaars, A.; Heijnen, C. J. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One 2016, 11, e0151890.Google Scholar
  36. [36]
    Perobelli, J. E. Effects of anticancer drugs in reproductive parameters of juvenile male animals and role of protective agents. Anticancer Agents Med. Chem., in press, DOI: 10.2174/1871520616666160219162033.Google Scholar
  37. [37]
    Glatter, O. A new method for the evaluation of small-angle scattering data. J. Appl. Crystallogr. 1977, 10, 415–421.CrossRefGoogle Scholar
  38. [38]
    Glatter, O. The interpretation of real-space information from small-angle scattering experiments. J. Appl. Crystallogr. 1979, 12, 166–175.CrossRefGoogle Scholar
  39. [39]
    Gao, J.; Wang, T.; Qiu, S.; Zhu, Y.; Liang, L.; Zheng, Y. Structure-based drug design of small molecule peptide deformylase inhibitors to treat cancer. Molecules 2016, 21, 396.CrossRefGoogle Scholar
  40. [40]
    Fukunishi, Y.; Mashimo, T.; Misoo, K.; Wakabayashi, Y.; Miyaki, T.; Ohta, S.; Nakamura, M.; Ikeda, K. Miscellaneous topics in computer-aided drug design: Synthetic accessibility and GPU computing, and other topics. Curr. Pharm. Des. 2016, 22, 3555–3568.CrossRefGoogle Scholar
  41. [41]
    Pandey, R. K.; Kumbhar, B. V.; Sundar, S.; Kunwar, A.; Prajapati, V. K. Structure-based virtual screening, molecular docking, ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase. J. Recept. Signal Transduct. Res., in press, DOI: 10.3109/10799893.2016.1171344.Google Scholar
  42. [42]
    Andreichenko, K. S.; Prylutska, S. V.; Medynska, K. O.; Bogutska, K. I.; Nurishchenko, N. E.; Prylutskyy, Y. I.; Ritter, U.; Scharff, P. Effect of fullerene C60 on ATPase activity and superprecipitation of skeletal muscle actomyosin. Ukr. Biochim. Zh. 2013, 85, 20–26.CrossRefGoogle Scholar
  43. [43]
    Xu, X.; Li, R. B.; Ma, M.; Wang, X.; Wang, Y. H.; Zou, H. F. Multidrug resistance protein P-glycoprotein does not recognize nanoparticle C60: Experiment and modeling. Soft Matter 2012, 8, 2915–2923.CrossRefGoogle Scholar
  44. [44]
    Liu, X. Y.; Liu, S. P.; Jiang, J.; Zhang, X.; Zhang, T. Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by downregulating expression of P-glycoprotein. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 1098–1108.Google Scholar
  45. [45]
    Pastan, I.; Gottesman, M. M.; Ueda, K.; Lovelace, E.; Rutherford, A. V.; Willingham, M. C. A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc. Natl. Acad. Sci. USA 1988, 85, 4486–4490.CrossRefGoogle Scholar
  46. [46]
    Leslie, E. M.; Deeley, R. G.; Cole, S. P. C. Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 2005, 204, 216–237.CrossRefGoogle Scholar
  47. [47]
    Sreenivasan, S.; Ravichandran, S.; Vetrivel, U.; Krishnakumar, S. In vitro and In silico studies on inhibitory effects of curcumin on multi drug resistance associated protein (MRP1) in retinoblastoma cells. Bioinformation 2012, 8, 13–19.CrossRefGoogle Scholar
  48. [48]
    Li, Q. C.; Liang, Y.; Hu, G. R.; Tian, Y. Enhanced therapeutic efficacy and amelioration of cisplatin-induced nephrotoxicity by quercetin in 1,2-dimethyl hydrazine-induced colon cancer in rats. Indian J. Pharmacol. 2016, 48, 168–171.CrossRefGoogle Scholar
  49. [49]
    Kovach, J. S.; Moertel, C. G.; Schutt, A. J.; Reitemeier, R. G.; Hahn, R. G. Phase II study of cis-diamminedichloroplatinum (NSC-119875) in advanced carcinoma of the large bowel. Cancer Chemother. Rep. 1973, 57, 357–359.Google Scholar
  50. [50]
    Friedlander, M.; Kaye, S. B.; Sullivan, A.; Atkinson, K.; Elliott, P.; Coppleson, M.; Houghton, R.; Solomon, J.; Green, D.; Russell, P. et al. Cervical-carcinoma: A drug-responsive tumor—experience with combined cisplatin, vinblastine, and bleomycin therapy. Gynecol. Oncol. 1983, 16, 275–281.CrossRefGoogle Scholar
  51. [51]
    Prestayko, A. W.; D’Aoust, J. C.; Issell, B. F.; Crooke, S. T. Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat. Rev. 1979, 6, 17–39.CrossRefGoogle Scholar
  52. [52]
    Hashmi, H.; Maqbool, A.; Ahmed, S.; Ahmed, A.; Sheikh, K.; Ahmed, A. Concurrent cisplatin-based chemoradiation in squamous cell carcinoma of cervix. J. Coll. Physicians Surg. Pak. 2016, 26, 302–305.Google Scholar
  53. [53]
    Jendželovská, Z.; Jendželovský, R.; Hilovská, L.; Koval, J.; Mikeš, J.; Fedorocko, P. Single pre-treatment with hypericin, a St. John’s wort secondary metabolite, attenuates cisplatin-and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells. Toxicol. in Vitro 2014, 28, 1259–1273.CrossRefGoogle Scholar
  54. [54]
    Xu, H.-W.; Xu, L.; Hao, J.-H.; Qin, C.-Y.; Liu, H. Expression of P-glycoprotein and multidrug resistanceassociated protein is associated with multidrug resistance in gastric cancer. J. Int. Med. Res. 2010, 38, 34–42.CrossRefGoogle Scholar
  55. [55]
    Lin, X. J.; Howell, S. B. DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance. Mol. Cancer Ther. 2006, 5, 1239–1247.CrossRefGoogle Scholar
  56. [56]
    Sui, X.; Luo, C.; Wang, C.; Zhang, F. W.; Zhang, J. Y.; Guo, S. W. Graphene quantum dots enhance anticancer activity of cisplatin via increasing its cellular and nuclear uptake. Nanomedicine 2016, 12, 1997–2006.Google Scholar
  57. [57]
    He, G. D.; He, G. L.; Zhou, R. Y.; Pi, Z. B.; Zhu, T. Q.; Jiang, L. M.; Xie, Y. B. Enhancement of cisplatin induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. Biochem. Biophys. Res. Commun. 2016, 469, 1075–1082.CrossRefGoogle Scholar
  58. [58]
    Desbois, N.; Pertuit, D.; Moretto, J.; Cachia, C.; Chauffert, B.; Bouyer, F. cis-Dichloroplatinum(II) complexes tethered to dibenzo[c,h][1,6]_naphthyridin-6-ones: Synthesis and cytotoxicity in human cancer cell lines in vitro. Eur. J. Med. Chem. 2013, 69, 719–727.CrossRefGoogle Scholar
  59. [59]
    Lee, Y.; Kim, Y. J.; Choi, Y. J.; Lee, J. W.; Lee, S.; Chung, H. W. Enhancement of cisplatin cytotoxicity by benzyl isothiocyanate in HL-60 cells. Food Chem. Toxicol. 2012, 50, 2397–2406.CrossRefGoogle Scholar
  60. [60]
    Roy, M.; Mukherjee, S. Reversal of resistance towards cisplatin by curcumin in cervical cancer cells. Asian Pac. J. Cancer Prev. 2014, 15, 1403–1410.CrossRefGoogle Scholar
  61. [61]
    Neumann, W.; Crews, B. C.; Sárosi, M. B.; Daniel, C. M.; Ghebreselasie, K.; Scholz, M. S.; Marnett, L. J.; Hey-Hawkins, E. Conjugation of cisplatin analogues and cyclooxygenase inhibitors to overcome cisplatin resistance. ChemMedChem 2015, 10, 183–192.CrossRefGoogle Scholar
  62. [62]
    Wang, T. H.; Wan, J. Y.; Gong, X.; Li, H. Z.; Cheng, Y. Tetrandrine enhances cytotoxicity of cisplatin in human drugresistant esophageal squamous carcinoma cells by inhibition of multidrug resistance-associated protein 1. Oncol. Rep. 2012, 28, 1681–1686.Google Scholar
  63. [63]
    Pariente, R.; Pariente, J. A.; Rodríguez, A. B.; Espino, J. Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: Effects on oxidative stress and DNA fragmentation. J. Pineal Res. 2016, 60, 55–64.CrossRefGoogle Scholar
  64. [64]
    Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene 2012, 31, 1869–1883.CrossRefGoogle Scholar
  65. [65]
    Ormerod, M. G.; O’Neill, C. F.; Robertson, D.; Harrap, K. R. Cisplatin induces apoptosis in a human ovarian carcinoma cell line without concomitant internucleosomal degradation of DNA. Exp. Cell Res. 1994, 211, 231–237.CrossRefGoogle Scholar
  66. [66]
    Ma, S. H.; Tan, W. H.; Du, B. T.; Liu, W.; Li, W. J.; Che, D. H.; Zhang, G. M. Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression. Mol. Med. Rep. 2016, 13, 3342–3348.Google Scholar
  67. [67]
    Golunski, G.; Woziwodzka, A.; Iermak, I.; Rychlowski, M.; Piosik, J. Modulation of acridine mutagen ICR191 intercalation to DNA by methylxanthines-analysis with mathematical models. Bioorg. Med. Chem. 2013, 21, 3280–3289.CrossRefGoogle Scholar
  68. [68]
    Woziwodzka, A.; Gwizdek-Wisniewska, A.; Piosik, J. Caffeine, pentoxifylline and theophylline form stacking complexes with IQ-type heterocyclic aromatic amines. Bioorg. Chem. 2011, 39, 10–17.CrossRefGoogle Scholar
  69. [69]
    Woziwodzka, A.; Golunski, G.; Wyrzykowski, D.; Kazmierkiewicz, R.; Piosik, J. Caffeine and other methylxanthines as interceptors of food-borne aromatic mutagens: Inhibition of Trp-P-1 and Trp-P-2 mutagenic activity. Chem. Res. Toxicol. 2013, 26, 1660–1673.CrossRefGoogle Scholar
  70. [70]
    Golunski, G.; Borowik, A.; Derewonko, N.; Kawiak, A.; Rychlowski, M.; Woziwodzka, A.; Piosik, J. Pentoxifylline as a modulator of anticancer drug doxorubicin. Part II: Reduction of doxorubicin DNA binding and alleviation of its biological effects. Biochimie 2016, 123, 95–102.Google Scholar
  71. [71]
    Golunski, G.; Borowik, A.; Lipinska, A.; Romanik, M.; Derewonko, N.; Woziwodzka, A.; Piosik, J. Pentoxifylline affects idarubicin binding to DNA. Bioorg. Chem. 2016, 65, 118–125.CrossRefGoogle Scholar
  72. [72]
    Orel, V.; Shevchenko, A.; Romanov, A.; Tselepi, M.; Mitrelias, T.; Barnes, C. H. W.; Burlaka, A.; Lukin, S.; Shchepotin, I. Magnetic properties and antitumor effect of nanocomplexes of iron oxide and doxorubicin. Nanomedicine 2015, 11, 47–55.Google Scholar
  73. [73]
    Prylutska, S. V.; Korolovych, V. F.; Prylutskyy, Y. I.; Evstigneev, M. P.; Ritter, U.; Scharff, P. Tumor-inhibitory effect of C60 fullerene complex with doxorubicin. Nanomed. Nanobiol. 2015, 2, 49–53.Google Scholar
  74. [74]
    Liu, X. X.; Liu, Y.; Hao, J. J.; Zhao, X. L.; Lang, Y. Z.; Fan, F.; Cai, C.; Li, G. Y.; Zhang, L. J.; Yu, G. L. In vivo anti-cancer mechanism of low-molecular-weight fucosylated chondroitin sulfate (LFCS) from sea cucumber Cucumaria frondosa. Molecules 2016, 21, 625.CrossRefGoogle Scholar
  75. [75]
    Xu, Y. Z.; Li, Y. H.; Lu, W. J.; Lu, K.; Wang, C. T.; Li, Y.; Lin, H. J.; Kan, L. X.; Yang, S. Y.; Wang, S. Y. et al. YL4073 is a potent autophagy-stimulating antitumor agent in an in vivo model of Lewis lung carcinoma. Oncol. Rep. 2016, 35, 2081–2088.Google Scholar
  76. [76]
    Peng, X. C.; Chen, X. X.; Zhang, Y.; Wang, H. J.; Feng, Y. A novel inhibitor of Rho GDP-dissociation inhibitor a improves the therapeutic efficacy of paclitaxel in Lewis lung carcinoma. Biomed. Rep. 2015, 3, 473–477.Google Scholar
  77. [77]
    Fan, S. J.; Xu, Y.; Li, X.; Tie, L.; Pan, Y.; Li, X. J. Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: In silico, in vitro and in vivo studies. Biochim. Biophys. Acta 2014, 1842, 1742–1754.CrossRefGoogle Scholar
  78. [78]
    Niu, P. G.; Zhang, Y. X.; Shi, D. H.; Liu, Y.; Chen, Y. Y.; Deng, J. Cardamonin inhibits metastasis of Lewis lung carcinoma cells by decreasing mTOR activity. PLoS One 2015, 10, e0127778.Google Scholar
  79. [79]
    Liu, Y. Z.; Yang, C. M.; Chen, J. Y.; Liao, J. W.; Hu, M. L. Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice. J. Nutr. Biochem. 2015, 26, 607–615.CrossRefGoogle Scholar
  80. [80]
    Das, S. K.; Eder, S.; Schauer, S.; Diwoky, C.; Temmel, H.; Guertl, B.; Gorkiewicz, G.; Tamilarasan, K. P.; Kumari, P.; Trauner, M. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011, 333, 233–238.CrossRefGoogle Scholar
  81. [81]
    Tsoli, M.; Robertson, G. Cancer cachexia: Malignant inflammation, tumorkines, and metabolic mayhem. Trends Endocrinol. Metab. 2013, 24, 174–183.CrossRefGoogle Scholar
  82. [82]
    Porporato, P. E. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 2016, 5, e200.CrossRefGoogle Scholar
  83. [83]
    Perego, P.; Righetti, S. C.; Supino, R.; Delia, D.; Caserini, C.; Carenini, N.; Bedogné, B.; Broome, E.; Krajewski, S.; Reed, J. C. et al. Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines. Apoptosis 1997, 2, 540–548.CrossRefGoogle Scholar
  84. [84]
    Jinushi, M. Immune regulation of therapy-resistant niches: Emerging targets for improving anticancer drug responses. Cancer Metastasis Rev. 2014, 33, 737–745.CrossRefGoogle Scholar
  85. [85]
    D’Arena, G.; Deaglio, S.; Laurenti, L.; de Martino, L.; de Feo, V.; Fusco, B. M.; Carella, A. M.; Cascavilla, N.; Musto, P. Targeting regulatory T cells for anticancer therapy. Mini Rev. Med. Chem. 2011, 11, 480–485.CrossRefGoogle Scholar
  86. [86]
    Shurin, M. R.; Naiditch, H.; Gutkin, D. W.; Umansky, V.; Shurin, G. V. ChemoImmunoModulation: Immune regulation by the antineoplastic chemotherapeutic agents. Curr. Med. Chem. 2012, 19, 1792–1803.CrossRefGoogle Scholar
  87. [87]
    Skivka, L. M.; Fedorchuk, O. G.; Bezdeneznykh, N. O.; Lykhova, O. O.; Semesiuk, N. I.; Kudryavets, Y. I.; Malanchuk, O. M. The effect of antineoplastic drug NSC63150 on immunogenicity of B16 melanoma. J. Exp. Integr. Med. 2014, 4, 93–105.CrossRefGoogle Scholar
  88. [88]
    Fedorchuk, O. G.; Pyaskovskaya, O. M.; Skivka, L. M.; Gorbik, G. V.; Trompak, O. O.; Solyanik, G. I. Paraneoplastic syndrome in mice bearing high-angiogenic variant of Lewis lung carcinoma: Relations with tumor derived VEGF. Cytokine 2012, 57, 81–88.CrossRefGoogle Scholar
  89. [89]
    Yang, X. L.; Ebrahimi, A.; Li, J.; Cui, Q. J. Fullerenebiomolecule conjugates and their biomedicinal applications. Int. J. Nanomedicine 2014, 9, 77–92.CrossRefGoogle Scholar
  90. [90]
    Turabekova, M.; Rasulev, B.; Theodore, M.; Jackman, J.; Leszczynska, D.; Leszczynski, J. Immunotoxicity of nanoparticles: A computational study suggests that CNTs and C60 fullerenes might be recognized as pathogens by Toll-like receptors. Nanoscale 2014, 6, 3488–3495.CrossRefGoogle Scholar
  91. [91]
    Prylutska, S. V.; Grynyuk, I. I.; Grebinyk, S. M.; Matyshevska, O. P.; Prylutskyy, Y. I.; Ritter, U.; Siegmund, C.; Scharff, P. Comperative study of biological action of fullerenes C60 and carbon nanotubes in thymus cells. Materialwiss. Werkstofftech. 2009, 40, 238–241.CrossRefGoogle Scholar
  92. [92]
    Prylutskyy, Y. I.; Petrenko, V. I.; Ivankov, O. I.; Kyzyma, O. A.; Bulavin, L. A.; Litsis, O. O.; Evstigneev, M. P.; Cherepanov, V. V.; Naumovets, A. G.; Ritter, U. On the origin of C60 fullerene solubility in aqueous solution. Langmuir 2014, 30, 3967–3970.CrossRefGoogle Scholar
  93. [93]
    Ritter, U.; Prylutskyy, Y. I.; Evstigneev, M. P.; Davidenko, N. A.; Cherepanov, V. V.; Senenko, A. I.; Marchenko, O. A.; Naumovets, A. G. Structural features of highly stable reproducible C60 fullerene aqueous colloid solution probed by various techniques. Fullerenes, Nanotubes, Carbon Nanostruct. 2015, 23, 530–534.CrossRefGoogle Scholar
  94. [94]
    Blanton, T. N.; Barnes, C. L.; Lelental, M. Preparation of silver behenate coatings to provide low-to mid-angle diffraction calibration. J. Appl. Cryst. 2000, 33, 172–173.CrossRefGoogle Scholar
  95. [95]
    Franke, D.; Kikhney, A. G.; Svergun, D. I. Automated acquisition and analysis of small angle X-ray scattering data. Nucl. Inst. Meth. Phys. Res. Sect. A 2012, 689, 52–59.CrossRefGoogle Scholar
  96. [96]
    Svergun, D. I. Determination of the regularization parameter in indirect-transform methods using perceptual criteria. J. Appl. Cryst. 1992, 25, 495–503.CrossRefGoogle Scholar
  97. [97]
    Li, J. Z.; Jaimes, K. F.; Aller, S. G. Refined structures of mouse P-glycoprotein. Protein Sci. 2014, 23, 34–46.CrossRefGoogle Scholar
  98. [98]
    Ramaen, O.; Leulliot, N.; Sizun, C.; Ulryck, N.; Pamlard, O.; Lallemand, J. Y.; van Tilbeurgh, H.; Jacquet, E. Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site. J. Mol. Biol. 2006, 359, 940–949.CrossRefGoogle Scholar
  99. [99]
    Vedadi, M.; Lew, J.; Artz, J.; Amani, M.; Zhao, Y.; Dong, A. P.; Wasney, G. A.; Gao, M.; Hills, T.; Brokx, S. et al. Genome-scale protein expression ans structural biology of Plasmodium falciparum and related Apicomplexan organisms. Mol. Biochem. Parasit. 2007, 151, 100–110.CrossRefGoogle Scholar
  100. [100]
    Warren, G. L.; Andrews, C. W.; Capelli, A. M.; Clarke, B.; LaLonde, J.; Lambert, M. H.; Lindvall, M.; Nevins, N.; Semus, S. F.; Senger, S. et al. A critical assessment of docking programs and scoring functions. J. Med. Chem. 2006, 49, 5912–5931.CrossRefGoogle Scholar
  101. [101]
    McMartin, C.; Bohacek, R. S. QXP: Powerful, rapid computer algorithms for structure-based drug design. J. Comput. Aided Mol. Des. 1997, 11, 333–344.CrossRefGoogle Scholar
  102. [102]
    Walker, P. R.; Kwast-Welfeld, J.; Gourdeau, H.; Leblanc, J.; Neugebauer, W.; Sikorska, M. Relationship between apoptosis and the cell cycle in lymphocytes: Roles of protein kinase C, tyrosine phosphorylation, and AP1. Exp. Cell Res. 1993, 207, 142–151.CrossRefGoogle Scholar
  103. [103]
    Mortelmans, K.; Zeiger, E. The Ames Salmonella/microsome mutagenicity assay. Mutat. Res. 2000, 455, 29–60.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Svitlana Prylutska
    • 1
  • Rostyslav Panchuk
    • 2
  • Grzegorz Gołuński
    • 3
  • Larysa Skivka
    • 1
  • Yuriy Prylutskyy
    • 1
    Email author
  • Vasyl Hurmach
    • 1
  • Nadya Skorohyd
    • 2
  • Agnieszka Borowik
    • 3
  • Anna Woziwodzka
    • 3
  • Jacek Piosik
    • 3
    Email author
  • Olena Kyzyma
    • 1
    • 4
  • Vasil Garamus
    • 5
  • Leonid Bulavin
    • 1
  • Maxim Evstigneev
    • 6
    Email author
  • Anatoly Buchelnikov
    • 6
  • Rostyslav Stoika
    • 2
  • Walter Berger
    • 7
  • Uwe Ritter
    • 8
  • Peter Scharff
    • 8
  1. 1.Taras Shevchenko NationalUniversity of KyivKyivUkraine
  2. 2.Institute of Cell BiologyNAS of UkraineLvivUkraine
  3. 3.Laboratory of BiophysicsIntercollegiate Faculty of Biotechnology UG-MUGGdańskPoland
  4. 4.Joint Institute for Nuclear ResearchDubna, Moscow reg.Russia
  5. 5.Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal ResearchGeesthachtGermany
  6. 6.Belgorod State UniversityBelgorodRussia
  7. 7.Institute of Cancer Research and Comprehensive Cancer CenterMedical University ViennaViennaAustria
  8. 8.Institute of Chemistry and BiotechnologyTechnical University of IlmenauIlmenauGermany

Personalised recommendations