title: Small compound 6-O-angeloylplenolin induces mitotic arrest and exhibits therapeutic potentials in multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells.
  
  
  RESULTS
  MM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats.
  
  
  CONCLUSIONS
  These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.
authors.affiliation: Guangzhou Institute of Biomedicine and Health and State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Chen
authors.forename: Heng-Xing
authors.initials: HX
authors.lastname: Liang
authors.forename: Feng-Xiang
authors.initials: FX
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.forename: Yong-Long
authors.initials: YL
authors.lastname: Chen
authors.forename: Yong-Xian
authors.initials: YX
authors.lastname: Cheng
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C509025:6-O-angeloylprenolin; D001897:Boronic Acids; D056744:Cyclin B1; D015850:Interleukin-6; D007783:Lactones; D020011:Protective Agents; D011719:Pyrazines; D012717:Sesquiterpenes; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin