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A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

DOI: 10.1039/C4CP05183A DOI Help

Authors: Paula M. Marques (University of Coimbra, Portugal) , Diego Gianolio (Diamond Light Source) , Giannantonio Cibin (Diamond Light Source) , John Tomkinson (ISIS Facility/STFC) , Stewart Parker (ISIS) , Rosendo Valero (University of Coimbra, Portugal) , R. Pedro Lopes (University of Coimbra, Portugal) , Luis Batista De Carvalho (University of Coimbra)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Physical Chemistry Chemical Physics , VOL 17 (7) , PAGES 5155 - 5171

State: Published (Approved)
Published: January 2015
Diamond Proposal Number(s): 8434

Abstract: The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(II) centre, both in the cisplatin–purine (adenine and guanine) and cisplatin–glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug–purine adduct, and cisplatin’s preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP–A2], reflecting a somewhat weaker Pt–A binding relative to Pt–G. The role of glutathione on the drug’s pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal’s preference for glutathione’s sulfur over purine’s nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum’s first coordination sphere.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: B18-Core EXAFS

Other Facilities: No