TY - JOUR
T1 - Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines
AU - Terashima, Masato
AU - Sakai, Kazuko
AU - Togashi, Yosuke
AU - Hayashi, Hidetoshi
AU - De Velasco, Marco A.
AU - Tsurutani, Junji
AU - Nishio, Kazuto
PY - 2014
Y1 - 2014
N2 - Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC.
AB - Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC.
KW - 5-FU
KW - EMT
KW - Eribulin
KW - MET
KW - S-1
KW - TNBC
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UR - http://www.scopus.com/inward/citedby.url?scp=84920904841&partnerID=8YFLogxK
U2 - 10.1186/2193-1801-3-417
DO - 10.1186/2193-1801-3-417
M3 - Article
AN - SCOPUS:84920904841
VL - 3
SP - 1
EP - 11
JO - SpringerPlus
JF - SpringerPlus
SN - 2193-1801
IS - 1
M1 - 417
ER -