The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

• Published in: Breast cancer research and treatment 2018-08, Vol.171 (1), p.43-52
• Main Authors: Ono, Hisako, Sowa, Yoshihiro, Horinaka, Mano, Iizumi, Yosuke, Watanabe, Motoki, Morita, Mie, Nishimoto, Emi, Taguchi, Tetsuya, Sakai, Toshiyuki
• Format: Article
• Language: English
• Subjects: Analysis; Antitumor agents; Apoptosis; Apoptosis - drug effects; Bcl-x protein; bcl-X Protein - genetics; bcl-X Protein - metabolism; Breast cancer; Cancer metastasis; Cancer research; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Drug Synergism; Drug therapy; Female; Flow cytometry; Furans - pharmacology; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humans; Ketones - pharmacology; MAP kinase; Medical schools; Medicine; Medicine & Public Health; Metastases; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Oncology; Patients; Peptides, Cyclic - pharmacology; Preclinical Study; Prognosis; Signal Transduction - drug effects; Survivin; Survivin - genetics; Survivin - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-018-4815-x

Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. Methods We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. Results The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. Conclusion We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.