Abstract
The clinically widely-used anticancer drug, cisplatin, binds strongly to DNA as a DNA-damaging agent. Herein, we investigated the interaction of cisplatin with a 15-mer single-stranded C,T-rich oligodeoxynucleotide, 5′-CCTT4CTT7G8C9T10TCTCC-3′ (ODN15), using ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) in conjunction with tandem mass spectrometry (top-down MS). Top-down MS analysis with collision-induced dissociation (CID) fragmentation of the mono-platinated and di-platinated ODN15 provided abundant and informative Pt-containing or Pt-free a/[a − B], w and internal fragments, allowing the unambiguous identification of T4, T7, C9, and T10 as the platination sites on the cisplatin-ODN15 adducts. These results revealed that, in addition to the well-established guanine site, the unexpected thermodynamic binding of cisplatin to cytosine and thymine bases was also evident at the oligonucleotide level. Furthermore, the binding models of cisplatin with cytosine and thymine bases were built as the Pt coordinated to cytosine-N(3) and thymine-N(3) with displacement of the proton or tautomerization of thymine. These findings contribute to a better understanding of the mechanism of action of cisplatin and its preference for gene loci when the drug binds to cellular DNA, and also demonstrate the great potential and superiority of FT-ICR MS in studying the interactions of metallodrugs with large biomolecules.
Highlights
Cisplatin, a representative of metal-based anticancer agents, is one of the most widely used chemotherapy drugs for clinical treatment against various cancers [1]
During the preparation of such ODN adducts, we found more than one cisplatin moiety binding to ODN15, which suggested that T or C might be platinated besides G
We applied negative-ion mass spectrometry to investigate the interactions between cisplatin and
Summary
A representative of metal-based anticancer agents, is one of the most widely used chemotherapy drugs for clinical treatment against various cancers [1]. DNA is generally accepted to be the primary target for cisplatin, which binds to DNA bases and forms platinum-DNA adducts [2,3]. A large number of studies have demonstrated that the binding sites of cisplatin to DNA and the generated structural alteration of DNA duplex play a crucial. The accurate localization of DNA binding sites of cisplatin would contribute to better elucidating the mechanism of action of this drug and its preference for gene loci when it binds to cellular DNA. Cisplatin has been demonstrated to bind to the purine-N(7) of guanine and adenine residues on DNA, mainly forming 1,2-intrastrand crosslinks between adjacent two guanines (1,2-d(GpG),
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