Modulation of tamoxifen-induced apoptosis by peripheral benzodiazepine receptor ligands in breast cancer cells.
The peripheral benzodiazepine receptor (PBR), an integral protein of the mitochondrial membrane, is involved in the formation of mitochondrial permeability transition (MPT) pores. The opening of the MPT-leading to the dissipation of the inner-mitochondrial transmembrane potential (deltapsi(m))-is considered to be an early apoptotic event. Therefore, we investigated the effect of the high-affinity PBR ligands Ro5-4684 and PK 11195 on tamoxifen (TAM)-induced apoptosis in MCF-7 and BT-20 breast cancer cell lines. Application of 100 nM TAM led to induction of apoptosis in both cell lines. Estrogene receptor (ER)-positive MCF-7 cells arrested in G(2/M) by TAM treatment showed no general dissipation of deltapsi(m), but reduction of deltapsi(m) was observed in a population of cells with high deltapsi(m). In ER-negative BT-20 cells TAM treatment induced no arrest of the cell cycle but dissipation of deltapsi(m). In both cell lines, nanomolar concentrations of the PBR ligands, which showed minor pro-apoptotic action themselves, reduced TAM-induced decrease of deltapsi(m) and apoptosis. In MCF-7 cells, a reduction of bcl-2 protein expression by TAM treatment was abolished by a combination of TAM with PBR ligands. Bax protein expression in BT-20 cells showed a significant increase in TAM-treated cells after 24hr but was not increased when treated with TAM and PBR ligands. From these findings, we concluded that binding of PBR ligands in nanomolar concentrations protects cells against apoptosis.
Strohmeier
Renate
R
Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Universitätsfrauenklinik, Theordor-Stern Kai 7, Frankfurt, Germany.
Roller
Marc
M
Sänger
Nicole
N
Knecht
Rainald
R
Kuhl
Herbert
H
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D001570:Benzodiazepinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D004347:Drug Interactions; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D001570:Benzodiazepinones; D007546:Isoquinolines; D011963:Receptors, GABA-A; D013629:Tamoxifen; C028513:4'-chlorodiazepam; C037850:PK 11195