title: Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells.
abstract: BACKGROUND
  Tamoxifen resistance is common in estrogen receptor-α (ERα)-positive breast cancers. Pawpaw and soursop are anticancer annonaceous plants in complementary medicine. Thus, we studied the effects of annonacin, an annonaceous acetogenin, in breast cancer cells.
  
  
  METHODS
  Cell growth and ERα-related pathways were studied. The effects of annonacin were tested in MCF-7 xenografts in nude mice.
  
  
  RESULTS
  In ERα-positive MCF-7 cells, annonacin (half-effective dose ED(50) = 0.31 μM) and 4-hydroxytamoxifen (ED(50) = 1.13 μM) decreased cell survival whereas annonacin (0.5-1 μM) increased cell death at 48 h. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival. Annonacin (0.1 μM) induced G(0)/G(1) growth arrest while increasing p21(WAF1) and p27(kip1) and decreasing cyclin D1 protein expression. Annonacin (0.1μM) decreased cyclin D1 protein expression more than 4-hydroxytamoxifen (1 μM). Annonacin (0.1 μM) increased apoptosis while decreasing Bcl-2 protein expression. The combination of annonacin (0.1 μM) and 4-hydroxytamoxifen (1 μM) decreased Bcl-2 protein expression and ERα transcriptional activity more than annonacin (0.1 μM) did alone. Annonacin, but not 4-hydroxytamoxifen, decreased ERα protein expression. Moreover, annonacin decreased phosphorylation of ERK1/2, JNK and STAT3. In nude mice, annonacin decreased MCF-7 xenograft tumor size at 7-22 days. Moreover, annonacin decreased ERα, cyclin D1 and Bcl-2 protein expression in the xenograft at 22 days.
  
  
  CONCLUSIONS
  Annonacin induced growth arrest and apoptosis in ERα-related pathways in MCF-7 cells. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival and ERα transcriptional activity. Moreover, annonacin attenuated MCF-7 xenograft tumor growth while inhibiting ERα, cyclin D1 and Bcl-2 protein expressions in nude mice.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Ko
authors.forename: Tung-Ying
authors.initials: TY
authors.lastname: Wu
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.forename: Jinn-Yuh
authors.initials: JY
authors.lastname: Guh
authors.forename: Lea-Yea
authors.initials: LY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D005663:Furans; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013629:Tamoxifen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C016601:afimoxifene; C053442:annonacin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases