Skip to main content
SpringerLink
Log in

Pixantrone anticancer drug as a DNA ligand: Depicting the mechanism of action at single molecule level

  • Regular Article
  • Published:
The European Physical Journal E Aims and scope Submit manuscript

Abstract.

In this work we use single molecule force spectroscopy performed with optical tweezers in order to characterize the complexes formed between the anticancer drug Pixantrone (PIX) and the DNA molecule, at two very different ionic strengths. Firstly, the changes of the mechanical properties of the DNA-PIX complexes were studied as a function of the drug concentration in the sample. Then, a quenched-disorder statistical model of ligand binding was used in order to determine the physicochemical (binding) parameters of the DNA-PIX interaction. In particular, we have found that the PIX molecular mechanism of action involves intercalation into the double helix, followed by a significant compaction of the DNA molecule due to partial neutralization of the phosphate backbone. Finally, this scenario of interaction was quantitatively compared to that found for the related drug Mitoxantrone (MTX), which binds to DNA with a considerably higher equilibrium binding constant and promotes a much stronger DNA compaction. The comparison performed between the two drugs can bring clues to the development of new (and more efficient) related compounds.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. G.A. Curt, Oncologist 1, 120i (1996)

    Google Scholar 

  2. F.R. Nascimento, T.A. Moura, J.V.P.B. Baeta, B.C. Publio, P.M.F. Ferreira, A.A. Santos, A.A.P. Franca, M.S. Rocha, G. Diaz-Munoz, M.A.N. Diaz, Biophys. Chem. 239, 1 (2018)

    Article  Google Scholar 

  3. B.B. Hasinoff, X. Wu, D. Patel, R. Kanagasabai, S. Karmahapatra, J.C. Yalowich, J. Pharmacol. Exp. Ther. 356, 397 (2016)

    Article  Google Scholar 

  4. N. Adnan, D.P. Buck, B.J. Evison, S.M. Cutts, D.R. Phillips, J.G. Collins, Org. Biomol. Chem. 8, 5359 (2010)

    Article  Google Scholar 

  5. B.J. Evison, O.C. Mansour, E. Menta, D.R. Phillips, S.M. Cutts, Nucl. Acids Res. 35, 3581 (2007)

    Article  Google Scholar 

  6. P. Menna, E. Salvatorelli, G. Minotti, Chem. Res. Toxicol. 29, 1270 (2016)

    Article  Google Scholar 

  7. G. Minotti, H. Han, V. Cattan, A. Egorov, F. Bertoni, Exp. Rev. Hematol. 11, 587 (2018)

    Article  Google Scholar 

  8. S.K. Konda, H. Wang, S.M. Cutts, D.R. Phillips, J.G. Collins, Org. Biomol. Chem. 13, 5972 (2015)

    Article  Google Scholar 

  9. B.J. Evison, R.A. Bilardi, F.C.K. Chiu, G. Pezzoni, D.R. Phillips, S.M. Cutts, Nucl. Acids Res. 37, 6355 (2009)

    Article  Google Scholar 

  10. S.K. Konda, C. Kelso, P.P. Pumuye, J. Medan, B.E. Sleebs, S.M. Cutts, D.R. Phillips, J.G. Collins, Org. Biomol. Chem. 14, 4728 (2016)

    Article  Google Scholar 

  11. K.R. Chaurasiya, T. Paramanathan, M.J. McCauley, M.C. Williams, Phys. Life Rev. 7, 299 (2010)

    Article  ADS  Google Scholar 

  12. M.S. Rocha, Integr. Biol. 7, 967 (2015)

    Article  Google Scholar 

  13. A. Sischka, K. Tönsing, R. Eckel, S.D. Wilking, N. Sewald, R. Rios, D. Anselmetti, Biophys. J. 88, 404 (2005)

    Article  ADS  Google Scholar 

  14. R. Eckel, R. Ros, A. Ros, S.D. Wilking, N. Sewald, D. Anselmetti, Biophys. J. 85, 1968 (2003)

    Article  Google Scholar 

  15. R. Krautbauer, L.H. Pope, T.E. Schrader, S. Allen, H.E. Gaub, FEBS Lett. 510, 154 (2002)

    Article  Google Scholar 

  16. R. Krautbauer, S. Fischerländer, S. Allen, H.E. Gaub, Single Mol. 3, 97 (2002)

    Article  ADS  Google Scholar 

  17. M.J. McCauley, M.C. Williams, Biopolymers 85, 154 (2007)

    Article  Google Scholar 

  18. M.J. McCauley, M.C. Williams, Biopolymers 91, 265 (2009)

    Article  Google Scholar 

  19. K. Pant, R.L. Karpel, I. Rouzina, M.C. Williams, J. Mol. Biol. 336, 851 (2004)

    Article  Google Scholar 

  20. J. Camunas-Soler, M. Manosas, S. Frutos, J. Tulla-Puche, F. Albericio, F. Ritort, Nucl. Acids Res 43, 2767 (2015)

    Article  Google Scholar 

  21. J.F. Marko, E.D. Siggia, Macromolecules 28, 8759 (1995)

    Article  ADS  Google Scholar 

  22. C.H.M. Lima, G.O. Almeida, M.S. Rocha, Biochim. Biophys. Acta Gen. Subj. 1862, 1107 (2018)

    Article  Google Scholar 

  23. E.F. Silva, R.F. Bazoni, E.B. Ramos, M.S. Rocha, Biopolymers 107, e22998 (2017)

    Article  Google Scholar 

  24. L. Siman, I.S.S. Carrasco, J.K.L. da Silva, M.C. Oliveira, M.S. Rocha, O.N. Mesquita, Phys. Rev. Lett. 109, 248103 (2012)

    Article  ADS  Google Scholar 

  25. A.V. Hill, Proc. Physiol. Soc. 40, iv (1910)

    Google Scholar 

  26. V.A. Bloomfield, Biopolymers 44, 269 (1997)

    Article  Google Scholar 

  27. V.A. Bloomfield, Curr. Opin. Struct. Biol. 6, 334 (1996)

    Article  Google Scholar 

  28. K. Yoshikawa, M. Takahashi, V.V. Vasilevskaya, A.R. Khokhlov, Phys. Rev. Lett. 76, 3029 (1996)

    Article  ADS  Google Scholar 

  29. M.S. Rocha, M.C. Ferreira, O.N. Mesquita, J. Chem. Phys. 127, 105108 (2007)

    Article  ADS  Google Scholar 

  30. H. Fritzsche, H. Triebel, J.B. Chaires, N. Dattagupta, D.M. Crothers, Biochemistry 21, 3940 (1982)

    Article  Google Scholar 

  31. L.S. Rosenberg, M.J. Carvlin, T.R. Krugh, Biochemistry 25, 1002 (1986)

    Article  Google Scholar 

  32. M. Enache, A.M. Toader, M.I. Enache, Molecules 21, 1356 (2016)

    Article  Google Scholar 

  33. V.A. Bloomfield, Biopolymers 31, 1471 (1991)

    Article  Google Scholar 

  34. N. Grønbech-Jensen, R.J. Mashl, R.F. Bruinsma, W.M. Gelbart, Phys. Rev. Lett. 78, 2477 (1997)

    Article  ADS  Google Scholar 

  35. R.G. Winkler, M. Gold, P. Reineker, Phys. Rev. Lett. 80, 3731 (1998)

    Article  ADS  Google Scholar 

  36. M. Khan, B. Jönsson, Biopolymers 49, 121 (1999)

    Article  Google Scholar 

  37. J.B. Chaires, N. Dattagupta, D.M. Crothers, Biochemistry 21, 3927 (1982)

    Article  Google Scholar 

  38. I. Rouzina, V.A. Bloomfield, Biophys. J. 74, 3152 (1998)

    Article  ADS  Google Scholar 

  39. R.F. Bazoni, C.H.M. Lima, E.B. Ramos, M.S. Rocha, Soft Matter 11, 4306 (2015)

    Article  ADS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratório de Física Biológica, Departamento de Física, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil

    C. H. M. Lima, J. M. Caquito Jr., R. M. de Oliveira & M. S. Rocha

Authors
  1. C. H. M. Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. M. Caquito Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. M. de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. S. Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. S. Rocha.

Additional information

Publisher’s Note

The EPJ Publishers remain neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lima, C.H.M., Caquito, J.M., de Oliveira, R.M. et al. Pixantrone anticancer drug as a DNA ligand: Depicting the mechanism of action at single molecule level. Eur. Phys. J. E 42, 130 (2019). https://doi.org/10.1140/epje/i2019-11895-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1140/epje/i2019-11895-6

Keywords

Search

Navigation