title: Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90.
abstract: BACKGROUND
  Multiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined.
  
  
  RESULTS
  In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat.
  
  
  CONCLUSIONS
  Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.
authors.affiliation: Department of Stress Medicine, Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, Beijing 100850, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhu
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Zhang
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Du
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Xu
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D047310:Apigenin / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018833:Chaperonins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047310:Apigenin; D047390:Casein Kinase II; D018833:Chaperonins