Binding mechanism of anti-cancer chemotherapeutic drug mitoxantrone to DNA characterized by magnetic tweezers

Journal of Nanobiotechnology
Dennis KreftDario Anselmetti

Abstract

Chemotherapeutic agents (anti-cancer drugs) are small cytostatic or cytotoxic molecules that often bind to double-stranded DNA (dsDNA) resulting in modifications of their structural and nanomechanical properties and thus interfering with the cell proliferation process. We investigated the anthraquinone compound mitoxantrone that is used for treating certain cancer types like leukemia and lymphoma with magnetic tweezers as a single molecule nanosensor. In order to study the association of mitoxantrone with dsDNA, we conducted force-extension and mechanical overwinding experiments with a sensitivity of 10-14 N. Using this method, we were able to estimate an equilibrium constant of association Ka ≈ 1 × 105 M-1 as well as a binding site size of n ≈ 2.5 base pairs for mitoxantrone. An unwinding angle of mitoxantrone-intercalation of ϑ ≈ 16° was determined. Moreover, we observed a complex concentration-dependent bimodal binding behavior, where mitoxantrone associates to dsDNA as an intercalator and groove binder simultaneously at low concentrations and as a mere intercalator at high concentrations.

References

Sep 1, 1979·Journal of Medicinal Chemistry·K C MurdockR V Citarella
Jan 1, 1985·Investigational New Drugs·R J White, F E Durr
Jan 1, 1985·Investigational New Drugs·L E PosnerK Cartwright
Dec 15, 1985·Biochemical Pharmacology·J Kapuscinski, Z Darzynkiewicz
Jul 28, 1968·Journal of Molecular Biology·W Müller, D M Crothers
Sep 9, 1994·Science·C BustamanteS Smith
Feb 1, 1994·Biochemistry·C J RocheD M Crothers
Mar 29, 1996·Science·T R StrickV Croquette
Aug 1, 1997·Hematology and Cell Therapy·X Thomas, E Archimbaud
Apr 17, 1998·Biophysical Journal·T R StrickV Croquette
Dec 31, 2003·Bioorganic & Medicinal Chemistry Letters·Ruel E McKnightDabney W Dixon
Feb 14, 2004·The Journal of Biological Chemistry·Belinda S ParkerDon R Phillips
Apr 20, 2004·CNS Drugs·Lesley J Scott, David P Figgitt
May 1, 2007·Nature Methods·Ioana D VladescuMark C Williams
Mar 17, 2009·Journal of Biomedical Science·Zahra Hajihassan, Azra Rabbani-Chadegani
Nov 18, 2009·Biophysical Journal·Christoph KleimannDario Anselmetti
Jun 1, 2010·Nucleic Acids Research·Katrin GüntherRalf Seidel
Jul 6, 2010·Nucleic Acids Research·Domenico SalernoFrancesco Mantegazza
Jul 14, 2010·Nucleic Acids Research·Jan LipfertNynke H Dekker
Jun 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Mark D SzczelkunRalf Seidel
Apr 18, 2016·Nucleic Acids Research·Ali A AlmaqwashiMark C Williams
Oct 21, 2016·Biophysical Journal·Ying WangDario Anselmetti
Mar 3, 2017·European Biophysics Journal : EBJ·Ying WangDario Anselmetti
Aug 2, 2017·Biochimica Et Biophysica Acta. General Subjects·Ying WangXavier Fernàndez-Busquets
Apr 1, 1968·Biopolymers·Donald M Crothers

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Citations

Nov 11, 2020·Proceedings of the National Academy of Sciences of the United States of America·Katelyn E Zulauf, James E Kirby
Apr 27, 2021·Journal of Biomolecular Structure & Dynamics·Sundararajan PonkarpagamKuppanagounder P Elango
Sep 2, 2021·The Journal of Physical Chemistry. B·Ishani MukherjeePradipta Purkayastha

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Methods Mentioned

BETA
electrophoresis
force measurements

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