title: Combination of 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity.
abstract: This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
authors.forename: Yu-Chong
authors.initials: YC
authors.lastname: Peng
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Lu
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Zhong
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Xie
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: You
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China. pengnfu2013@163.com.
authors.forename: Ning-Fu
authors.initials: NF
authors.lastname: Peng
authors.affiliation: Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China. xitongpingjia@163.com.
authors.forename: Le-Qun
authors.initials: LQ
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005472:Fluorouracil
keywords: 2-Morpholino-8-phenyl-4H-chromen-4-one; 5-Fluorouracil (5-FU); Cancer stem cell; Liver cancer; p-AKT