Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic             agents in uterine cervical cancer cell lines.
Although the prognosis of uterine cervical cancer has improved due to the             advances of treatment modalities, survival of recurrent or metastatic cervical             cancer remains poor. Cisplatin is an effective radiosensitizer, but its single             agent activity in recurrent cervical cancer is disappointing. Inactivation of             tumor suppressors through ubiquitin-mediated degradation by human papillomavirus             is known to be a critical step in the carcinogenesis of uterine cervix. Bortezomib,             a selective inhibitor of the proteasome, has been shown to inhibit the growth             of several solid tumors. To determine the role of bortezomib in cervical cancer             as a chemotherapeutic agent, we studied its biological properties. Bortezomib             efficiently inhibited the proteasomal activities in cervical cancer cells, and             an increased expression of tumor suppressors such as p53, hDlg and hScrib became             evident. In addition, sequential or concomitant treatment of bortezomib and cisplatin             stimulated the expression of p53, hScrib and p21 and the stimulation was markedly             influenced by the order of drugs in HeLa cells. We further confirmed that the             concomitant use of bortezomib and cisplatin has synergistic inhibitory effects             on the growth of xenograft tumors derived from HeLa cells. Our data establish             the possibility that the concomitant use of bortezomib and cisplatin could be             an alternative choice in cases resistant to conventional chemotherapy, and sequential             effects must be considered for advanced and therapy-resistant cervical cancer             patients.
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Yuichiro
Y
Miyamoto
Shunsuke
S
Nakagawa
Osamu
O
Wada-Hiraike
Takayuki
T
Seiki
Michihiro
M
Tanikawa
Haruko
H
Hiraike
Kenbun
K
Sone
Kazunori
K
Nagasaka
Katsutoshi
K
Oda
Kei
K
Kawana
Keiichi
K
Nakagawa
Tomoyuki
T
Fujii
Tetsu
T
Yano
Shiro
S
Kozuma
Yuji
Y
Taketani
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D001897:Boronic Acids; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; D011719:Pyrazines; C480591:SCRIB protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin