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Year:
1999
| Volume: 7
| Issue: 4
| Pages: 153-157
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Original Article |
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IN VITRO ANALYSES OF ANTIPROLIFERATIVE ACTIVITY OF NOVEL PLATINUM(II) COMPLEXES WITH SULFUR-CONTAINING LIGANDS ON MCF7 HUMAN BREAST CANCER CELL LINE
Vesna KOJIC, Gordana BOGDANOVIC, Tatjana SRDIC, Dimitar JAKIMOV, Zivadin D. BUGARCIC, Milos I. DJURAN, Dragana CETOJEVIC-SIMIN, Mirjana BALTIC, Vukudin LEOVAC |
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DOI:
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Abstract: |
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Background: The effects of two novel cisplatin analogues: cis-[Pt(CH3SCH2CH2SCH3)Cl2] (Pt1) and cis-[Pt(DMSO)2Cl2] (Pt2) on growth, induction of apoptosis and cell-cycle parameters of MCF7 human breast cancer cell line analysed alone or simultaneously with Taxol are presented in this paper.
Material and Methods: The platinum(II) complexes, cis-dichloro-1, 2-bis(methylthio)ethaneplatinum(II), (Pt1) and cis-dichlorobis(dimethylsulfoxide)platinum(II), (pt2) cisplatin(cisPt) and Taxol have been tested at different equimolar concentrations. Cells were exposed to complexes for 2h and left to recover in fresh medium for 24h, 48h or 72h. 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 Pt complex as well as combination index (CI; Pt complex + Taxol) for various cytotoxicity levels were determined by median effects analysis.
Results: MCF7 cells were found to be sensitive to both Pt complexes. The novel 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 its all concentrations at all recovery periods. A plateau effect was achieved three days after the treatmentat at Pt1 concentrations <= 1microM. Pt2 , however, decreased MCF7 cells survival only for the first 24h ranging between 50-55%. Pt2 cytotoxicity sharply decreased thereafter, approaching 2h - treatment cytotoxicity level. The median IC50 values for Pt1 and Pt2 were similar (0.337 and 0.3051microM, respectively) but only for the first 24h. The IC50 values for Pt1 strongly depend on the recovery period. On simultaneous exposure of cells to Taxol and Pt 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 Pt complex induced apoptosis in MCF7 cells. The level of apoptosis correlated with cytotoxicity level for the range concentrations. Both Pt complexes, at IC50 concentrations, increased the number of MCF7 cells in G0G1 phase of cell cycle. Pt2-treated cells remained arrested in G0G1 phase up to 72 h after the treatment. Combination of Pt2 and Taxol caused further arrest of cells in G0G1 phase (24h) parallel with strong decrement of G2M phase cells.
Conclusion: This study showed that two novel Pt complexes containing sulfur thio ligands influence the MCF7 cells growth more effectively as compared to the parent drug. They differ however, 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. |
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Key words:
Platinum complexes; Cell growth; Apoptosis; Cell cycle; Breast cancer cell line |
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