Abstract
Background
Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens.
Methods
A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4-hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays.
Results
The 50 % growth inhibitory concentrations of eribulin were 0.38–2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43–1.46 for ER-positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1–S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines.
Discussion
The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells.
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Acknowledgments
Esai Co. kindly provided us with eribulin for this study. We thank Dr. Yasumitsu Nishimura and Dr. Takemi Otsuki of the Department of Hygiene, Kawasaki Medical School for their technical advice. We also thank Mrs. Kaoru Tsuboi and Ms. Megumi Ogo for their technical assistance. This work was supported by Research Project Grants from Kawasaki Medical School (25-12 and 26-5) and by Research Grants from Eisai Co. and the Ministry of Education, Culture, Sports, Science, and Technology, Japan (23591911 and 26461964).
Conflict of interest
Junichi Kurebayashi received a research grant from Esai Co. The other authors declare that they have no conflict of interest.
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Kurebayashi, J., Kanomata, N., Yamashita, T. et al. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. Breast Cancer 23, 425–436 (2016). https://doi.org/10.1007/s12282-014-0580-9
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DOI: https://doi.org/10.1007/s12282-014-0580-9