In the present study we found

In the present study, we found that stathmin was significantly down-regulated upon treatment with a combination of Zol and gefitinib. The down-regulation of stathmin, which was not detected by 2-D DIGE after treatment with either agent alone, was considered to be attributable to cooperative effect of Zol and gefitinib. Down-regulation of endogenous stathmin by transfection with an adenovirus expressing stathmin small interfering RNA (siRNA) was reported to decrease the migration of HT1080 (human fibrosarcoma) gaboxadol through fibronectin-coated Transwells [23]. Silencing of stathmin by siRNA has also been shown to decrease the proliferation, viability, or invasion of cancer cells derived from malignancies of the prostate [30], breast [31], stomach [24], and colon [26]. These findings are in accord with our present data indicating that down-regulation of stathmin paralleled the inhibition of both cell proliferation and invasion of the bone-seeking clone upon combined treatment with Zol and gefitinib, suggesting that stathmin could be a potential candidate for therapeutic target for inhibition of bone metastasis. Finally, our data allow us to propose a potentially promising strategy for cancer therapy. Down-regulation of stathmin has been reported to enhance the sensitivity to anti-microtubule drugs [32–34]. Because the combined treatment of Zol and gefitinib down-regulates the expression of stathmin, a further inhibitory effect against breast cancer might be expected if anti-microtubule drugs were to be added. Although a preclinical study would be needed to investigate this triple strategy, synergistic anti-angiogenic effects of stathmin inhibition and taxol exposure have already been reported [35]. Combination of these three agents might be indicated for patients with aggressive breast cancers such as those with the triple negative phenotype.
Acknowledgments We are grateful to Mr. Masahiro Hashimoto and Mr. Yoshiyuki Itoh, Japan Electron Optics Laboratory (JEOL) Co., Ltd., Akishima, Tokyo, Japan, for providing the data of mass spectrometric analysis, and Ms. Kozue Suzuki for skilled assistance with protein labeling and loading for 2D-DIGE. This study was supported in part by the Foundation for Promotion of Cancer Research, a Ministry of Defense Grant (Osamu Matsubara and Keiichi Iwaya), by a Grant-in-aid for Scientific Research (C) (KAKENHI24590457) and by the National Cancer Center Research and Development Fund (23-A-11).
Introduction Patients with breast cancer bone metastasis may be treated with a combination of chemotherapy, often an anthracyclin, in addition to the potent anti-resorptive bisphosphonate (BP) zoledronic acid. The optimisation of combination therapy in this setting has been the subject of a number of in vitro and in vivo studies. The majority of these have shown beneficial effects of BPs, alone or in addition to standard therapy, of a variety of tumours in and outside bone (reviewed in [1,2]). A comprehensive comparison of the bone studies suggests that improved outcome may require earlier initiation of BP treatment schedule than that currently recommended for patients with metastatic bone disease [1]. We have found that even small tumour colonies induce major changes to the microenvironment before overt osteolysis is detected [3]. Early intervention may therefore be necessary to inhibit homing and growth of the tumour cells at the metastatic site. The clinical relevance of bisphosphonates as anti-cancer agents has been subject to considerable debate and results relating to anti-tumour effects from clinical trials of bisphosphonates have been conflicting, with some reporting direct anti-tumour effects [4,5] and some not [6]. However, the recently reported AZURE trial demonstrated that adjuvant zoledronic acid combined with chemotherapy in high-risk breast cancer patients did not result in increased overall survival in all patients [7]. Surprisingly, post-menopausal women did benefit from adjuvant zoledronic acid, with approximately 30% increase in overall survival compared to those receiving chemotherapy alone, suggesting that the endocrine environment plays a key role in determining the response to therapy. The cellular and molecular mechanisms responsible for this differential effect remain to be established, and there is clearly a need for more detailed investigations of effects of therapy on the bone microenvironment.