Growth effects of some platinum(Ii) complexes with sulfur-containing carrier ligands on MCF7 human breast cancer cell line upon simultaneous administration with taxol

Abstract

The platinum (II) complexes, cis-[PtCl 2 (CH 3 SCH 2 CH 2 SCH 3 )] (Pt1), cis-[PtCl 2 (dmso) 2 ] (dmso is dimethylsulfoxide; Pt2) and cis-[PtCl 2 (NH 3 ) 2 ] (cisplatin), and taxol (T) have been tested at different equimolar concentrations. Cells were exposed to complexes for 2 h and left to recover in fresh medium for 24, 48 or 72 h. Growth inhibition was measured by tetrazolium WST1 assay. Analyses of the cell cycle and apoptosis were performed by flow cytometry, at the same exposure times. The IC50 value of each platinum(II) complex as well as combination index (CI; platinum(II) complex + taxol) for various cytotoxicity levels were determined by median effects analysis. MCF7 cells were found to be sensitive to both Ptl and Pt2 complexes. These cisplatin analogues influenced the cell growth more effectively as compared to cisplatin. Cytotoxic effect was concentration and time-dependent. Profound growth inhibitory effect was observed for Pt1 complex, across all its concentrations at all recovery periods. A plateau effect was achieved three days after treatment at Pt1 concentrations ≤ 1 μM. Pt2 , however, decreased MCF7 cells survival only for the first 24 h ranging between 50-55%. Pt2 cytotoxicity sharply decreased thereafter, approaching 2 h - treatment cytotoxicity level. The median IC50 values for Pt1 and Pt2 were similar (0.337 and 0.3051 μM, respectively) but only for the first 24 h. The IC50 values for Ptl strongly depend on the recovery period. On simultaneous exposure of cells to taxol and platinum(II) complexes no consistent effect was found. The CIs for combinations of taxol with Pt1 or Pt2 revealed cytotoxic effects that were in most cases synergistic (Pt1) or less than additive (Pt2). Flow cytometry analysis has shown that each platinum(II) complex induced apoptosis in MCF7 cells. The level of apoptosis correlated with cytotoxicity level for the range concentrations. Both cisplatin analogues, at IC50 concentrations, increased the number of MCF7 cells in GOG1 phase of cell cycle. Pt2-treated cells remained arrested in GOG1 phase up to 72 h after treatment. Combination of Pt2 and taxol caused further arrest of cells in GOG1 phase (24 h) in parallel with strong decrement of G2M phase cells. This study showed that two cisplatin analogues, Pt1 and Pt2, with sulfur-containing carrier ligands, influence the MCF7 cells growth more effectively as compared to the parent drug. They differ in their cytotoxicity profiles and in their interaction with taxol as well. The cell cycle changes and induction of apoptosis in MCF7 cells implicate a programmed cell death pathway in cell-killing.