Abstract
Purpose: To evaluate the in vitro and in vivo effects of the combination therapy of histone deacetylases (HDAsC) inhibitor, chidamide, and bromodomain-containing proteins (BETs) inhibitor, PFI-1, on triplenegative breast cancer (TNBC).
 Methods: Four distinct breast cancer cell lines and one TNBC mouse model were treated with vehicle, chidamide, PFI-1 alone, or chidamide and PFI-1. The inhibitory effect of chidamide or PFI-1 on HDACs and BETs was assessed by HDAC enzyme inhibition and AlphaScreen assays. Cell viability was determined by MTT assay while protein expression of p-STAT3 was evaluated by western blotting and immunohistochemistry (IHC) staining assay.
 Results: Chidamide exerted inhibitory effect on HDACs while PFI-1 inhibited BET proteins. The threedimensional model demonstrated the interactions between chidamide and HDAC2, and between PFI-1 and BRD4. Chidamide or PFI-1 exerted inhibitory effects on breast cancer cell proliferation in vitro. However, the combination of PFI-1 and chidamide significantly inhibit MDA-MB-231 cell viability, and decrease the expression of p-STAT3, when compared to that treated with chidamide or PFI-1 alone. Moreover, the combined inhibitory effect of PFI-1 and chidamide on tumor growth was also found in the in vivo mice experiments.
 Conclusion: The combination of chidamide and PFI-1 is a potential is a potential therapeutic strategy for the management of TNBC.
 Keywords: Triple-negative breast cancer, Histone deacetylases, Bromodomain
Highlights
Triple-negative breast cancer (TNBC), with poor prognosis and high rate of metastasis, is a heterogeneous breast cancer subtype [1] that accounts for approximately 20 % of newly diagnosed primary breast cancers [2]
The synergistic effects of the HDACi chidamide and the BET inhibitors (BETi) PFI-1 used as a combination therapy in TNBC were investigated
The results in our study indicated that chidamide alone or PFI-1 alone elicits inhibitory effects on breast tumor cell viability
Summary
Triple-negative breast cancer (TNBC), with poor prognosis and high rate of metastasis, is a heterogeneous breast cancer subtype [1] that accounts for approximately 20 % of newly diagnosed primary breast cancers [2]. A study reported synergistic effects of HDACi and BETi in lymphoma, urothelial carcinoma, , non-small cell lung cancer, and breast cancer [14]. The synergistic effects of the HDACi chidamide and the BETi PFI-1 used as a combination therapy in TNBC were investigated. The base reaction buffer was composed of 137 mM NaCl, 50 mM Tris-HCl(pH 8.0), 2.7 mM KCl, and 1 mM MgCl2 to which was added fresh 1 mg/mL BSA and 1 % DMSO. Deacetylation was performed by the addition of 2× enzyme in wells of the reaction plate, into which buffer was added. Four milliliters of protein were added to 384-well plates, followed by nonbiotinylated peptides, solvents, or compounds. The plates were incubated at 25 °C for 25 min and 4 mL of biotinylated peptides were added. Cells were cultured in RPMI-1640, F12, or DMEM supplemented with fetal bovine serum (10 % FBS, Hyclone, Logan, UT, USA) and penicillin/streptomycin (1 %), and maintained in in an incubator (5 % CO2 at 37 °C)
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