title: Synergistic inhibition of characteristics of liver cancer stem-like cells with a combination of sorafenib and 8-bromo-7-methoxychrysin in SMMC-7721 cell line.
abstract: Sorafenib, a multi-kinase inhibitor, has shown its promising antitumor effect in a series of clinical trials, and has been approved as the current standard treatment for advanced hepatocellular carcinoma (HCC). 8-Bromo‑7-methoxychrysin (BrMC) is a novel chrysin synthetic analogue that has been reported to inhibit the growth of various tumor cells and possess properties for targeting liver cancer stem cells (LCSCs) . The present study investigated the synergistic targeting effects on the properties of liver cancer stem-like cells (LCSLCs) by a combination of sorafenib and BrMC in SMMC-7721 cell line. We also investigated whether this effect involves regulation of HIF-1α, Twist and NF-κB protein. We found that the sphere-forming cells (SFCs) from the SMMC‑7721 cells possessed the properties of LCSLCs. Sorafenib diminished the self-renewal capacity and downregulated the expression of stem cell biomarkers (CD133, CD44 and ALDH1) in a dose-dependent manner, while BrMC cooperated with sorafenib to strengthen this inhibition. Moreover, the combination of sorafenib and BrMC led to a remarkable decrease in the cellular migration and invasion, the downregulation of N-cadherin protein and upregulation of E-cadherin protein, and increase of cell apoptosis in LCSLCs. BrMC has a remarkable antagonistic effect on the upregulation of protein expression and DNA binding activity of NF-κB (p65) induced by sorafenib. In addition, our results indicated that the synergistic inhibition of sorafenib and BrMC on the characteristics of LCSLCs involves the downregulated expression of HIF-1α and EMT regulator Twist1. Collectively, the combination therapy of sorafenib and BrMC could be a new and promising therapeutic approach in the treatment of HCC.
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xiaozheng
authors.initials: X
authors.lastname: Cao
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Kaiqun
authors.initials: K
authors.lastname: Ren
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Meifang
authors.initials: M
authors.lastname: Quan
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Song
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, and Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
authors.affiliation: Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yaojin
authors.initials: Y
authors.lastname: Peng
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D005419:Flavonoids / Q000008:administration & dosage*; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib
chemical_list: C552860:8-bromo-7-methoxychrysin; D005419:Flavonoids; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib