[Inhibitory effect of carbamazepine on proliferation of estrogen-dependent breast cancer cells].
OBJECTIVE
Carbamazepine, which has been used as an anti-epileptic drug in clinic for many years, is currently recognized as a histone deacetylase inhibitor (HDI), most of which showed anti-tumor characteristics. This study was to investigate the inhibitory effect of carbamazepine on estrogen dependent breast cancer cell lines with estrogen receptor alpha (ERalpha) expression and further explore the underlying mechanisms.


METHODS
Sulforhodamine B viability assay was used to evaluate the viability of various cells treated with different drugs. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were performed to detect the protein and mRNA expression of ERalpha and Cyclin D1. Immunofluorescence assay was employed to observe HER-2 expression in MCF-7RT cells, which were resistant to tamoxifen. Immunoprecipitation was performed to detect the chaperon function and acetylation level of Hsp90.


RESULTS
Carbamazepine treatment could inhibit the proliferation of MCF-7 and T47D cells stimulated by estradiol (P<0.01). Carbamazepine and 4-hydroxytamoxifen (4-OHT) demonstrated a synergic effect on the inhibition of proliferation of MCF-7 cells stimulated by estradiol (q=1.00). Cabamazepine reversed the proliferation of MCF-7RT cells stimulated by 4-hydroxytamoxifen (P<0.01). Carbamazepine treatment could decrease the expression of ERalpha and Cyclin D1 at protein and mRNA level in ERalpha-positive cells and could reduce HER-2 expression in MCF-7RT cells. The decrease of ERalpha and Cyclin D1 expression was inhibited by MG132, an inhibitor of 26S proteosome. Carbamazepine treatment elevated the acetylation level of Hsp90 and disrupted its chaperon function.


CONCLUSIONS
Carbamazepine shows significant anti-proliferation effect in ERalpha-positive breast cancer cell lines and this might be due to the enhancement of proteosome-mediated degradation of ERalpha and Cyclin D1 by carbamazepine. Furthermore, carbamazepine could reverse HER-2 dependent drug resistance to 4-OHT by reducing HER-2 expression.
Meng
Qing-Wei
QW
The Fourth Department of Medicine Oncology, Affiliated Tumor Hospital, Harbin Medical University, Harbin, Heilongjiang, 150040, P. R. China.
Zhao
Chang-Hong
CH
Xi
Yu-Hui
YH
Cai
Li
L
Sun
Li-Chun
LC
Sui
Guang-Jie
GJ
D000107:Acetylation / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002220:Carbamazepine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D002220:Carbamazepine; D019938:Cyclin D1; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C016601:afimoxifene