title: Molecular mechanism of SAHA on regulation of autophagic cell death in tamoxifen-resistant MCF-7 breast cancer cells.
abstract: OBJECTIVE
  Tamoxifen is currently used for the treatment of estrogen receptor-positive breast cancer patients, but acquired resistance to tamoxifen is a critical problem in breast cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed HDAC inhibitor. The aim of this study is to investigate the anticancer effects of SAHA in tamoxifen-resistant MCF-7 (TAMR/MCF-7) cells.
  
  
  METHODS
  Cytotoxicity, apoptosis and autophagic cell death induced by SAHA were studied. A TAMR/MCF-7 cells xenograft model was established to investigate the inhibitory effect of SAHA on tumor growth in vivo.
  
  
  RESULTS
  SAHA inhibited the proliferation of TAMR/MCF-7 cells in a dose-dependent manner. SAHA significantly reduced the expression of HDAC1, 2, 3, 4 and 7 and increased acetylated histone H3 and H4. Although SAHA induced G2/M phase arrest of cell cycle, apoptotic cell death was very low, which is correlated with the slight change in the activation of caspases and PARP cleavage. Interestingly, expression of the autophagic cell death markers, LC3-II and beclin-1, was significantly increased in TAMR/MCF-7 cells treated with SAHA. Autophagic cell death induced by SAHA was confirmed by acridine orange staining and transmission electron microscopy (TEM) in TAMR/MCF-7 cells. In mice bearing the TAMR/MCF-7 cell xenografts, SAHA significantly reduced the tumor growth and weight, without apparent side effects.
  
  
  CONCLUSIONS
  These results suggest that SAHA can induce caspase-independent autophagic cell death rather than apoptotic cell death in TAMR/MCF-7 cells. SAHA-mediated autophagic cell death is a promising new strategy to treatment of tamoxifen-resistant human breast cancer.
authors.affiliation: Laboratory of Molecular Toxicology, College of Pharmacy, Pusan National University, Jangjeon-dong, Geumjeung-gu, Busan, Republic of Korea.
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: A Jin
authors.initials: AJ
authors.lastname: Won
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D061986:MCF-7 Cells; D051379:Mice; D013629:Tamoxifen / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013629:Tamoxifen; D000077337:Vorinostat; D006655:Histone Deacetylases