A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1006-1023. doi: 10.1080/14756366.2018.1471687.

Abstract

Six novel compounds of platinum(II) with pyrazole derivatives PtPz1-PtPz6 were synthesised and characterised (PtPz1 - [Pt2N-hydroksymethyl-3,5-dimethylpyrazole4(berenil)2]Cl4; PtPz2 - [Pt23,5-dimethylpyrazole4(berenil)2]Cl4; PtPz3 - [Pt23,4-dimethylpyrazole4(berenil)2]Cl4; PtPz4 - [Pt2pyrazole4(berenil)2]Cl4; PtPz5- [Pt25-methylpyrazole4(berenil)2]Cl4; PtPz6 - [Pt2N-ethylpyrazole4(berenil)2]Cl4). The cytotoxic activity of these complexes against MCF-7 and MDA-MB-231 breast cancer cell lines was determined using the MTT assay. Evaluation of apoptosis induction was done with the Annexin V-fluorescein isothiocyanate/propidium iodide assay. In addition, using a flow cytometer, we determined the influence of test compounds on the cell cycle and caspase-3, -8, and -9 activity. The obtained results of caspase activity were confirmed by cell imaging. Moreover, using the flow cytometer, the effects of the test compounds on mitochondrial potential change were assessed. The test results showed that novel pyrazole-platinum(II) complexes exhibited stronger anti-proliferative activity against two breast cancer cell lines than reference cisplatin. Compounds PtPz1, PtPz2, and PtPz3 with methyl substituents at the pyrazole ring showed stronger activity than pyrazole or ethylpyrazole containing complexes. Studies have shown that inhibition of cell survival occurs by arresting the G1 cell cycle and inducing apoptosis. Our analysis associated with the response of MCF-7 and MDA-MB-231 cells to treatment with PtPz1-PtPz6 showed that it leads the cells through the external and intrinsic (mitochondrial) apoptotic pathway via indirect DNA damage.

Keywords: Anti-cancer drugs; apoptosis; platinum complexes; pyrazole.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caspases / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Molecular Structure
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Pyrazoles
  • pyrazole
  • Caspases

Grants and funding

This study was conducted with the use of equipment purchased by the Medical University of Bialystok as part of the OP DEP 2007–2013, Priority Axis I0.3, contract No. POPW.01.03.00–20-022/09.