Characterization of the antiproliferative potential and biological targets of a trans ketoimine platinum complex

Joana Silva, António Sebastião Rodrigues, Paula A. Videira, Jamal Lasri, Adília Januário Charmier, Armando J L Pombeiro, Alexandra R. Fernandes

Research output: Contribution to journalArticle

Abstract

The characterization of the antiproliferative potential of the ketoimine platinum complex trans-[PtCl2{RC({double bond, long}O)N{double bond, long}CN-(H)C(Me)2-CH2CH2}2] (R = CH2CO2Me) is reported. It showed a higher cytotoxicity against HCT116 and HepG2 cancer cells (IC50 values of 22.74 ± 0.04 μM and 22.08 ± 0.08 μM, respectively) compared to fibroblasts and a non-tumorigenic cell line. It was also observed a moderate ability of the complex to induce apoptosis in HCT116 cells, as observed by fluorescence microscopy and flow cytometry. The observed antiproliferative activities of the complex are mostly due to delay in the cell cycle progression. In vitro DNA interaction studies revealed a DNA affinity constant of 6.67 × 105 M-1, suggesting a high affinity to DNA, by comparison to the value obtained for doxorubicin. A decrease in the electrophoretic mobility of the supercoiled plasmid DNA (pDNA) suggested the formation of complex-DNA adducts. However, the complex did not exhibit relevant genotoxicity in V79 cells. Proteomic assays demonstrated that the ketoimine Pt(II) complex promotes an overexpression of two negative cell cycle regulators, PA2G4 and 14-3-3σ, and PHB, and a decrease in expression of VDAC1 and HSP90B, probably associated with the antiproliferative potential. The ketoimine Pt(II) complex is able to trigger an overexpression of cytoskeleton-associated proteins in agreement with its ability to maintain cell structure, and an overexpression of oxidative stress enzymes, coping with the induction of ROS formation, observed by in vitro EMSA assays. In conclusion, the ketoimine Pt(II) complex is an antiproliferative agent with potential to be used against cancer cells. © 2014 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)156-167
JournalInorganica Chimica Acta
Volume423-Part B
Issue numberNA
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • Cancer
  • Cisplatin
  • Cytotoxicity
  • DNA
  • Selectivity
  • trans-Pt

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