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bioRxiv · 10.1101/398826

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

Batista de Carvalho, A. L. M.·Mamede, A. P.·Dopplapudi, A.·Garcia Sakai, V.·Doherty, J.·Frogley, M.·Cinque, G.·Gardner, P.·Gianolio, D.·Batista de Carvalho, L. A. E.·Marques, M. P. M.
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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.

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Batista de Carvalho, A. L. M., Mamede, A. P., Dopplapudi, A., Garcia Sakai, V., Doherty, J., Frogley, M., Cinque, G., Gardner, P., Gianolio, D., Batista de Carvalho, L. A. E., Marques, M. P. M.. 2018-08-23. Anticancer Drug Impact on DNA - A Study by Neutron Spectrocopy, Synchrotron-based FTIR and EXAFS. https://doi.org/10.1101/398826

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