Cell Biochemistry and Biophysics

, Volume 67, Issue 3, pp 1103–1113 | Cite as

PT-ACRAMTU, A Platinum–Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA

  • Samrat Dutta
  • Matthew J. Snyder
  • David Rosile
  • Kristen L. Binz
  • Eric H. Roll
  • Jimmy Suryadi
  • Ulrich Bierbach
  • Martin Guthold
Original Paper

Abstract

We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of non-classical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms mono-adducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (r b) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an r b of 0.15. At r b of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49–65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed.

Keywords

Acramtu Cancer drug DNA lengthening Persistence length 

Notes

Acknowledgments

We thank Lu Rao for technical support with DNA-drug incubations. This work was supported by the National Science Foundation [CMMI-0646627, to M.G.], the North Carolina Biotechnology Center [2011-MRG-1115, to M.G.], and the National Institutes of Health [CA101880, to U.B.].

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Samrat Dutta
    • 1
  • Matthew J. Snyder
    • 1
  • David Rosile
    • 1
  • Kristen L. Binz
    • 1
  • Eric H. Roll
    • 1
  • Jimmy Suryadi
    • 2
  • Ulrich Bierbach
    • 2
  • Martin Guthold
    • 1
  1. 1.Department of PhysicsWake Forest UniversityWinston-SalemUSA
  2. 2.Department of ChemistryWake Forest UniversityWinston-SalemUSA

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