Sublethal concentrations of the platinum(II) complex [Pt(O,O'-acac)(gamma-acac)(DMS)] alter the motility and induce anoikis in MCF-7 cells.

Abstract

BACKGROUND AND PURPOSE:

We showed previously that a new Pt(II) complex ([Pt(O,O'-acac)(gamma-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)(gamma-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)(gamma-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-epsilon and FAK, after [Pt(O,O'-acac)(gamma-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)(gamma-acac)(DMS)] provoked the generation of reactive oxygen species (ROS), and the activation of p38MAPK, Src and PKC-epsilon. p38MAPK phosphorylation, cell anoikis and migration due to [Pt(O,O'-acac)(gamma-acac)(DMS)] were blocked by PKC-epsilon inhibition. Furthermore, Src inhibition blocked the [Pt(O,O'-acac)(gamma-acac)(DMS)]-provoked activation of PKC-epsilon, while ROS generation blockage inhibited the activation of Src, and also the decrement of phosphorylated FAK observed in detached [Pt(O,O'-acac)(gamma-acac)(DMS)]-treated cells.

CONCLUSIONS AND IMPLICATIONS:

Sublethal concentrations of [Pt(O,O'-acac)(gamma-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)(gamma-acac)(DMS)] may be a promising therapeutic agent for preventing growth and metastasis of breast cancer.

• Authors: Antonella Muscella, Nadia Calabriso, Carla Vetrugno, Loredana Urso, Francesco Paolo Fanizzi, Sandra Angelica De Pascali, Santo Marsigliante
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 6 Pg. 1362-77 (Jul 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20590627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Pt(O,O'-acac)(gamma-acac)(DMS)
• Reactive Oxygen Species
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Anoikis (drug effects)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Female
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Neoplasm Metastasis (prevention & control)
• Organoplatinum Compounds (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)