title: Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurebayashi
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanomata
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shimo
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D004958:Estradiol; D004965:Estrogen Antagonists; D000077267:Fulvestrant; D005663:Furans; D007659:Ketones; D013629:Tamoxifen; C016601:afimoxifene; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Cancer stem cells; Eribulin; Fulvestrant; Tamoxifen