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A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines

par Vessières, Anne;Corbet, Cyril;Heldt, Jan Martin;Lories, Nicolas;Jouy, Nathalie;Laïos, Ioanna;Leclercq, Guy ;Jaouen, Gérard;Toillon, Robert-Alain
Référence Journal of inorganic biochemistry, 104, 5, page (503-511)
Publication Publié, 2010-05

Article révisé par les pairs

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Résumé :

The aim of this work was to investigate the mechanism of action of ferrocifen (Fc-OH-TAM), the ferrocenyl analog of 4-hydroxy-tamoxifen (OH-TAM), which is the active metabolite of tamoxifen, the drug most widely prescribed for treatment of hormone-dependent breast cancers. Fc-OH-TAM showed an anti-proliferative effect on the six breast cancer cell lines tested, 3 ERα positive (MCF-7, T-47D, ZR-75-1) and 3 ERα negative (MDA-MB-231, SKBR-3, Hs578-T) whatever their ER (estrogen receptor) status. However, the mechanism of action of the ferrocenyl derivative appeared to differ depending on the status of the ERα. Analysis of cell cycle distribution revealed that Fc-OH-TAM first recruits cells in the S phase in both ERα positive and ERα negative cells. In the presence of ERα, Fc-OH-TAM allowed cell cycle progression, with a subsequent blockade in G0/G1, whereas in the absence of ERα, cells remained in the S phase. Significant production of ROS was observed only in the presence of Fc-OH-TAM in both ERα positive and negative breast cancer cell lines. Within our experimental conditions, this ROS production is associated with cell cycle arrest and senescence rather than apoptosis. In the presence of ERα, Fc-OH-TAM seems to mainly act in the same way as OH-TAM but also induces an additional cytotoxic effect not mediated by the receptor. Our data suggest that this cytotoxic effect of Fc-OH-TAM is expressed via a mechanism of action distinct from the non-genomic pathway observed with high doses of OH-Tamoxifen. © 2010 Elsevier Inc.