A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines.
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 ERalpha positive (MCF-7, T-47D, ZR-75-1) and 3 ERalpha 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 ERalpha. Analysis of cell cycle distribution revealed that Fc-OH-TAM first recruits cells in the S phase in both ERalpha positive and ERalpha negative cells. In the presence of ERalpha, Fc-OH-TAM allowed cell cycle progression, with a subsequent blockade in G0/G1, whereas in the absence of ERalpha, cells remained in the S phase. Significant production of ROS was observed only in the presence of Fc-OH-TAM in both ERalpha 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 ERalpha, 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.
Vessières
Anne
A
CNRS UMR 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, France.
Corbet
Cyril
C
Heldt
Jan Martin
JM
Lories
Nicolas
N
Jouy
Nathalie
N
Laïos
Ioanna
I
Leclercq
Guy
G
Jaouen
Gérard
G
Toillon
Robert-Alain
RA
D000111:Acetylcysteine / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects; D005260:Female; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D005296:Ferrous Compounds; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; C514120:ferrocifen; D013629:Tamoxifen; C016601:afimoxifene; D000111:Acetylcysteine