Synergistic effects of danazol and mifepristone on the cytotoxicity of UCN-01 in hormone-responsive breast cancer cells.
BACKGROUND
7-Hydroxystaurosporine (UCN-01) is a novel antitumor agent as well as a potent inhibitor of a variety of protein kinases with a preference to protein kinase C. Because an intimate interaction exists between PKC signaling and the ER signaling pathways, sex steroid agonists/antagonists might modulate the cytotoxicity of UCN-01.


METHODS
Effects of sex steroid agonists and antagonists on the UCN-01 cytotoxicity were analyzed by MTT assay in MCF-7/WT and MCF-7/ADR, a multiple drug resistance phenotype lacking ER and PR.


RESULTS
MCF-7/ADR is 23-fold more resistant to UCN-01 than MCF-7. In MCF-7/WT, danazol and mifepristone enhanced the cytotoxicity of UCN-01, while these agents did not exert any significant effects on it in MCF-7/ADR.


CONCLUSIONS
These results suggest that danazol or mifepristone might enhance the antitumor activity of UCN-01 in hormone-dependent cancer cells by interacting with PR.
Yokoyama
Y
Y
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan. yokoyama@cc.gifu-u.ac.jp
Shinohara
A
A
Takahashi
Y
Y
Wan
X
X
Takahashi
S
S
Niwa
K
K
Tamaya
T
T
D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003613:Danazol / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000378:metabolism / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology; D015735:Mifepristone / Q000378:metabolism / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009640:Norethindrone / Q000378:metabolism / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D012739:Gonadal Steroid Hormones; D006727:Hormone Antagonists; D013629:Tamoxifen; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D005485:Flutamide; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D003613:Danazol; D009640:Norethindrone; D006854:Hydrocortisone