Abstract
Summary
Sagopilone, a fully synthetic epothilone and very potent anti-tumor agent, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. In addition to its antiproliferative effects, this study shows direct effects of sagopilone on bone resorption and osteoclast activity.
Introduction
Sagopilone, a novel fully synthetic third-generation epothilone, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. The aim of this study was to investigate whether the effect was primarily due to sagopilone’s antiproliferative effect and consequent inhibition of tumor cell growth, or if sagopilone exerts direct effects on bone resorption and osteoclast activity.
Methods
Sagopilone was studied and compared to paclitaxel in vitro in human osteoclast differentiation and activity cultures. For studying the potential of sagopilone for inhibiting bone resorption in vivo, a mouse model of ovariectomy (ovx)-induced osteoporosis was utilized.
Results
Sagopilone inhibited osteoclast differentiation and activity more efficiently than paclitaxel and showed less cytotoxicity. Whereas sagopilone showed inhibitory effects on human osteoclast differentiation and activity already at 5 and 15 nM, respectively, paclitaxel started to show effects only at 20 and 100 nM concentrations, respectively. Sagopilone treatment increased BMD In the mouse ovx model even though a non-optimized dose was used which is effective in tumor-bearing mice.
Conclusion
This is the first study to evaluate sagopilone’s effects on bone resorption in non-cancerous situation. The evidence that sagopilone is beneficial for bone will strengthen the status of sagopilone as an anti-cancer compound compared to other microtubule stabilizing agents.
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Acknowledgements
We thank Karola Henschel, Christine Morgenroth and Suvi Suutari for skilful technical assistance.
Conflicts of interest
Anne Strube, Dominik Mumberg and Ulrich Klar are employed by BayerSchering Pharma AG. Dominik Mumberg, Ulrich Klar and Sanna-Maria Käkönen are shareholders of BayerSchering Pharma AG. Mari Suominen, Jukka Rissanen and Jussi Halleen are shareholders of and employed by Pharmatest Services Ltd. S.-M. Käkönen is currently working for Amgen Inc.
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A. Strube and M. Suominen contributed equally to this work.
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Strube, A., Suominen, M.I., Rissanen, J.P. et al. The anti-tumor agent sagopilone shows antiresorptive effects both in vitro and in vivo. Osteoporos Int 22, 2887–2893 (2011). https://doi.org/10.1007/s00198-010-1486-9
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DOI: https://doi.org/10.1007/s00198-010-1486-9