Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1

  • Zhengyi Wu
  • Qin Liu
  • Xiao Liang
  • Xiaoliang Yang
  • Ningyan Wang
  • Xinghao Wang
  • Hongzhe Sun
  • Yi Lu
  • Zijian Guo
Original Paper

Abstract

Cellular uptake of platinum-based antitumor drugs is a critical step in the mechanism of the drug action and associated resistance, and deeper understanding of this step may inspire development of novel methods for new drugs with reduced resistance. Human copper transporter 1 (hCtr1), a copper influx protein, was recently found to facilitate the cellular entry of several platinum drugs. In the work reported here, we constructed a Met- and His-rich 20mer peptide (hCtr1-N20) corresponding to the N-terminal domain of hCtr1, which is the essential domain of hCtr1 for transporting platinum drugs. The interactions of the peptide with cisplatin and its analogues, including transplatin, carboplatin, oxaliplatin, and [Pt(l-Met)Cl2], were explored at the molecular level. Electrospray ionization (ESI) mass spectrometry (MS) data revealed that all of the platinum(II) complexes used in present study can bind to hCtr1-N20 in 1:1 and 2:1 stoichiometry. Four Met residues should be involved in binding to cis-platinum complexes on the basis of the tandem MS spectrometry and previously reported data. Time-dependent 2D [1H,15N] heteronuclear single quantum coherence NMR spectra indicate the reaction of cisplatin with hCtr1-N20 is a stepwise process. The intermediate, however, is transient, which is consistent with the ESI-MS results. Time-dependent ESI-MS data revealed that the geometry and the properties of both the leaving and the nonleaving groups of platinum(II) complexes play essential roles in controlling the reactivity and formation of the final products with hCtr1-N20.

Keywords

Antitumor drug Copper transporter Resistance Human copper transporter 1 Uptake 

Notes

Acknowledgments

Financial support from the National Natural Science Foundation of China (nos. 20631020, 90713001, and 20721002) and the Natural Science Foundation of Jiangsu Province (BK2008015) is gratefully acknowledged.

Supplementary material

775_2009_576_MOESM1_ESM.doc (250 kb)
Supplementary Figs. S1–S4 (DOC 250 kb)

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Copyright information

© SBIC 2009

Authors and Affiliations

  • Zhengyi Wu
    • 1
  • Qin Liu
    • 2
  • Xiao Liang
    • 1
  • Xiaoliang Yang
    • 1
  • Ningyan Wang
    • 3
  • Xinghao Wang
    • 4
  • Hongzhe Sun
    • 4
  • Yi Lu
    • 3
  • Zijian Guo
    • 1
  1. 1.State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical EngineeringNanjing UniversityNanjingPeople’s Republic of China
  2. 2.Department of Applied ChemistryNanjing University of Finance and EconomicsNanjingPeople’s Republic of China
  3. 3.Department of Chemistry, Beckman Institute for Advanced Science and TechnologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  4. 4.Department of Chemistry and Open Laboratory of Chemical BiologyThe University of Hong KongHong KongPeople’s Republic of China

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