Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Oncol Rep. 2013 Jan;29(1):51-7. doi: 10.3892/or.2012.2072. Epub 2012 Oct 5.
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.
尽管由于治疗方式的进步，子宫颈癌的预后有所改善，但复发性或转移性宫颈癌的生存率仍然较差。顺铂是一种有效的放射增敏剂，但在复发性宫颈癌中的单药活性令人失望。人乳头瘤病毒通过泛素介导的降解使肿瘤抑制因子失活，被认为是子宫颈癌发生的关键步骤。硼替佐米是蛋白酶体的选择性抑制剂，已被证明能抑制几种实体瘤的生长。为了确定硼替佐米作为化疗药物在宫颈癌中的作用，我们研究了它的生物学特性。硼替佐米能有效地抑制宫颈癌细胞中的蛋白酶体活性，并且肿瘤抑制因子如 p53、hDlg 和 hScrib 的表达增加。此外，硼替佐米和顺铂的序贯或同时治疗刺激了 p53、hScrib 和 p21 的表达，并且在 HeLa 细胞中药物顺序明显影响了刺激作用。我们进一步证实，硼替佐米和顺铂的联合使用对源自 HeLa 细胞的异种移植肿瘤的生长具有协同抑制作用。我们的数据确立了硼替佐米和顺铂联合使用可能是对常规化疗耐药病例的另一种选择的可能性，并且对于晚期和治疗耐药的宫颈癌患者必须考虑序贯效应。
