Anticancer Drug Impact on DNA – A Study by Neutron Spectroscopy coupled to Synchrotron-based FTIR and EXAFS

Research output: Contribution to conferencePaper

  • External authors:
  • Ana Batista de Carvalho
  • Adriana Mamede
  • Asha Dopplapudi
  • Victoria Garcia Sakai
  • James Doherty
  • Mark Frogley
  • Gianfelice Cinque
  • Diego Gianolio
  • Luís Batista de Carvalho
  • Maria Marques

Abstract

A complementary structural and dynamical information on drug-DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(II) and Pd(II) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled to synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA´s dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- and mid-infrared measurements allowed the first simultaneous detection of the drugs and its primary pharmacological target, as well as the drug-prompted changes in DNA´s conformation that mediate cytotoxicity. The local environment of the absorbing Pd(II) and Pt(II) centers in the drugs´ adducts with adenine, guanine and glutathione was attained by EXAFS.

Bibliographical metadata

Original languageEnglish
Number of pages14
Publication statusPublished - 2019