Background and purpose: We showed previously that a new Pt(II) complex ([Pt(O,O′-acac)(γ-acac)(DMS)]) exerted high and fast apoptotic processes in MCF-7 cells. The objective of this study was to investigate the hypothesis that [Pt(O,O′-acac)(γ-acac)(DMS)] is also able to exert anoikis and alter the migration ability of MCF-7 cells, and to show some of the signalling events leading to these alterations. Experimental approach: Cells were treated with sublethal doses of [Pt(O,O′-acac)(γ-acac)(DMS)], and the efficiency of colony initiation and anchorage-independent growth was assayed; cell migration was examined by in vitro culture wounding assay. Gelatin zymography for MMP-2 and -9 activities, Western blottings of MMPs, MAPKs, Src, PKC-ε and FAK, after [Pt(O,O′-acac)(γ-acac)(DMS)] treatment, were also performed. Key results: Sub-cytotoxic drug concentrations decreased the: (i) anchorage-dependent and -independent growth; (ii) migration ability; and (iii) expression and activity of MMP-2 and MMP-9. [Pt(O,O′-acac) (γ-acac)(DMS)] provoked the generation of reactive oxygen species (ROS), and the activation of p38MAPK, Src and PKC-ε. p38MAPK phosphorylation, cell anoikis and migration due to [Pt(O,O′-acac)(γ-acac)(DMS)] were blocked by PKC-ε inhibition. Furthermore, Src inhibition blocked the [Pt(O,O′-acac)(γ-acac)(DMS)]-provoked activation of PKC-ε, while ROS generation blockage inhibited the activation of Src, and also the decrement of phosphorylated FAK observed in detached [Pt(O,O′-acac) (γ-acac)(DMS)]-treated cells. Conclusions and implications: Sublethal concentrations of [Pt(O,O′-acac)(γ-acac)(DMS)] induced anoikis and prevented events leading to metastasis via alterations in cell migration, anchorage independency, stromal interactions and MMP activity. Hence, [Pt(O,O′-acac)(γ-acac)(DMS)] may be a promising therapeutic agent for preventing growth and metastasis of breast cancer. © 2010 The British Pharmacological Society.
Sublethal concentrations of the platinum(II) complex [Pt(O,O′-acac) (γ-acac)(DMS)] alter the motility and induce anoikis in MCF-7 cells
Urso L.;
2010
Abstract
Background and purpose: We showed previously that a new Pt(II) complex ([Pt(O,O′-acac)(γ-acac)(DMS)]) exerted high and fast apoptotic processes in MCF-7 cells. The objective of this study was to investigate the hypothesis that [Pt(O,O′-acac)(γ-acac)(DMS)] is also able to exert anoikis and alter the migration ability of MCF-7 cells, and to show some of the signalling events leading to these alterations. Experimental approach: Cells were treated with sublethal doses of [Pt(O,O′-acac)(γ-acac)(DMS)], and the efficiency of colony initiation and anchorage-independent growth was assayed; cell migration was examined by in vitro culture wounding assay. Gelatin zymography for MMP-2 and -9 activities, Western blottings of MMPs, MAPKs, Src, PKC-ε and FAK, after [Pt(O,O′-acac)(γ-acac)(DMS)] treatment, were also performed. Key results: Sub-cytotoxic drug concentrations decreased the: (i) anchorage-dependent and -independent growth; (ii) migration ability; and (iii) expression and activity of MMP-2 and MMP-9. [Pt(O,O′-acac) (γ-acac)(DMS)] provoked the generation of reactive oxygen species (ROS), and the activation of p38MAPK, Src and PKC-ε. p38MAPK phosphorylation, cell anoikis and migration due to [Pt(O,O′-acac)(γ-acac)(DMS)] were blocked by PKC-ε inhibition. Furthermore, Src inhibition blocked the [Pt(O,O′-acac)(γ-acac)(DMS)]-provoked activation of PKC-ε, while ROS generation blockage inhibited the activation of Src, and also the decrement of phosphorylated FAK observed in detached [Pt(O,O′-acac) (γ-acac)(DMS)]-treated cells. Conclusions and implications: Sublethal concentrations of [Pt(O,O′-acac)(γ-acac)(DMS)] induced anoikis and prevented events leading to metastasis via alterations in cell migration, anchorage independency, stromal interactions and MMP activity. Hence, [Pt(O,O′-acac)(γ-acac)(DMS)] may be a promising therapeutic agent for preventing growth and metastasis of breast cancer. © 2010 The British Pharmacological Society.
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