A trans-platinum(II) complex induces apoptosis in cancer stem cells of breast cancer

Bioorg Med Chem. 2017 Jan 1;25(1):269-276. doi: 10.1016/j.bmc.2016.10.032. Epub 2016 Oct 29.


Recent accumulating evidence has supported the notion that tumors have hierarchically organized heterogeneous cell populations and a small subpopulation of cells, termed cancer stem cells (CSCs), are responsible for tumor initiation, maintenance as well as drug resistance. Therefore, targeting the CSCs along with the other cancer cells has been the most important topic during the last decade. In the present study, we evaluated the cytotoxic activity of trans-[PtCl2(2-hepy)2] [2-hepy=2-(2-hydroxyethyl) pyridine] complex and the mechanism of cell death in breast CSCs. Stemness markers, Oct-4 and Sox2, were determined in mammospheres by western blotting. Cytotoxicity was assessed using the ATP viability assay. Cell death was fluorescently visualized and further confirmed by flow cytometry as well as gene expression analysis. The Pt(II) complex significantly reduced the cell viability, prevented mammosphere formation and disrupted mammosphere structures in a dose-dependent manner (0-100μM). The mode of cell death was apoptosis and it was shown by the presence of caspase 3/7 activity, Annexin V-FITC positivity, decreased mitochondrial membrane potential and increased expressions of pro-apoptotic genes (TNFRSF10A and HRK). Interestingly, necroptosis was also observed by the evidence of increased MLKL expression. In conclusion, the Pt(II) complex seems to be a highly promising anticancer compound due to its promising cytotoxic activity on CSCs. Therefore, it deserves in vivo further studies for the proof-of-concept.

Keywords: Anti-growth effect; Apoptosis; Breast cancer stem cells; Necroptosis; Platinum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Caspase Inhibitors / pharmacology
  • Cell Self Renewal / drug effects
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Necrosis
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / metabolism
  • Oligopeptides / pharmacology
  • Organoplatinum Compounds / pharmacology*
  • SOXB1 Transcription Factors / metabolism


  • Antineoplastic Agents
  • Caspase Inhibitors
  • Imidazoles
  • Indoles
  • Octamer Transcription Factor-3
  • Oligopeptides
  • Organoplatinum Compounds
  • POU5F1 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • benzyloxycarbonyl-valyl-alanyl-aspartic acid
  • dichloridobis(2-(2-hydroxyethyl)pyridine)platinum(II)
  • necrostatin-1