UCN-01 (7-hydroxystaurosporine) inhibits the growth of human breast cancer xenografts through disruption of signal transduction.
BACKGROUND
7-Hydroxystaurosporine (UCN-01), originally isolated as a phospholipid-dependent protein kinase C inhibitor, has been shown to have antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to S phase by inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor protein, leading to dephosphorylation of retinoblastoma (Rb) protein.


METHODS
The antitumor activity of UCN-01 has been investigated against three human breast carcinoma strains serially transplanted into nude mice, including estrogen-dependent MCF-7, Br-10, and estrogen-independent MX-1. When the inoculated tumors started growing exponentially, UCN-01 (7.5 mg/kg) was administered intraperitoneally on five consecutive days a week for 2 weeks. The antitumor effect was evaluated as the lowest T/C ratio (%) during the experiments, where T was the relative mean tumor weight of the treated group and C was that of the control group. At the end of UCN-01 administration expression of p21, a protein of the CDK inhibitor family, and phosphorylated and dephosphorylated Rb protein was detected by Western blotting using treated and control tumors.


RESULTS
UCN-01 had activity against MCF-7 and Br-10, with the lowest T/C ratios of 25.0% and 27.0%, respectively, while MX-1 was resistant to UCN-01 with a T/C ratio of 65.9%. The antitumor spectrum of UCN-01 was different from that of other conventional agents such as doxorubicin and cyclophosphamide which were ineffective against Br-10 but were active against MX-1. Although p21 was induced in three tested strains by UCN-01, little dephosphorylated Rb protein was expressed in MX-1 compared with Br-10 and MCF-7 (in vitro).


CONCLUSIONS
UCN-01 appeared to be a promising agent for the treatment of breast cancer, with a different mode of action and antitumor spectrum from other currently available antitumor drugs.
Department of Surgery, Saitama Social Insurance Hospital, 4-9-3, Kitaurawa, Saitama-shi, Japan. j-koh@jc4.so-net.ne.jp
Junichi
J
Koh
Tetsuro
T
Kubota
Tomofusa
T
Migita
Sadanori
S
Abe
Mitsumasa
M
Hashimoto
Yoichiro
Y
Hosoda
Masaki
M
Kitajima
D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004967:Estrogens; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000031:analogs & derivatives; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D000970:Antineoplastic Agents; D004967:Estrogens; C054852:7-hydroxystaurosporine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011493:Protein Kinase C; D019311:Staurosporine; D005472:Fluorouracil