Anticancer Drug Impact on DNA - A Study by Neutron Spectrocopy, Synchrotron-based FTIR and EXAFS

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. 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). The drug impact on DNAs 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 DNAs conformation that mediate cytotoxicity in DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231), a low prognosis type of cancer. 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.