Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines

Miyamoto,Yuichiro; Nakagawa,Shunsuke; Wada-Hiraike,Osamu; Seiki,Takayuki; Tanikawa,Michihiro; Hiraike,Haruko; Sone,Kenbun; Nagasaka,Kazunori; Oda,Katsutoshi; Kawana,Kei; Nakagawa,Keiichi; Fujii,Tomoyuki; Yano,Tetsu; Kozuma,Shiro; Taketani,Yuji

doi:10.3892/or.2012.2072

Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines

Authors:
- Yuichiro Miyamoto
- Shunsuke Nakagawa
- Osamu Wada-Hiraike
- Takayuki Seiki
- Michihiro Tanikawa
- Haruko Hiraike
- Kenbun Sone
- Kazunori Nagasaka
- Katsutoshi Oda
- Kei Kawana
- Keiichi Nakagawa
- Tomoyuki Fujii
- Tetsu Yano
- Shiro Kozuma
- Yuji Taketani
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Affiliations: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan, Department of Obstetrics and Gynecology, School of Medicine, Teikyo University, Tokyo 173-8605, Japan, Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Published online on: October 5, 2012 https://doi.org/10.3892/or.2012.2072
Pages: 51-57

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Abstract

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.

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