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


METHODS
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.


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
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.
Muscella
Antonella
A
Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento, Lecce, Italy.
Calabriso
Nadia
N
Vetrugno
Carla
C
Urso
Loredana
L
Fanizzi
Francesco Paolo
FP
De Pascali
Sandra Angelica
SA
Marsigliante
Santo
S
D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C527556:Pt(O,O'-acac)(gamma-acac)(DMS); D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9