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
- 380 Downloads
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.
KeywordsAntitumor drug Copper transporter Resistance Human copper transporter 1 Uptake
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.
- 14.Song IS, Savaraj N, Siddik ZH (2005) Mol Cancer Ther 4:864Google Scholar
- 17.Freeman HC, Golomb ML (1970) J Chem Soc D Chem Commun 1523–1524Google Scholar
- 18.Kerrison SJS, Sadler PJ (1977) J Chem Soc Chem Commun 861–863Google Scholar
- 19.Case DA, Darden TA, Cheatham TE I, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley MRCW, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hormak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA (2006) AMBER 9. University of California, San FranciscoGoogle Scholar
- 30.Weidt SK, Mackay CL, Langridge-Smith PRR, Sadler PJ (2007) Chem Commun 2542Google Scholar
- 41.Guo ZJ, Chen Y, Zang E, Sadler PJ (1997) J Chem Soc Dalton Trans 410:7–4111Google Scholar