title: Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma.
abstract: BACKGROUND
  Isothiocyanates, a family of phytochemicals found in cruciferous vegetables, have cytotoxic effects against several types of tumor cells. Multiple myeloma is a fatal disease characterized by clonal proliferation of plasma cells in the bone marrow. The growing body of preclinical information on the anti-cancer activity of isothiocyanates led us to investigate their anti-myeloma properties.
  
  
  METHODS
  We evaluated the anti-myeloma activity of the isothiocyanates, sulforaphane and phenethyl isothiocyanate, on a panel of human myeloma cell lines as well as primary myeloma tumor cells. Cell viability, apoptosis, cell cycle alterations and cell proliferation were then analyzed in vitro and in a xenograft mouse model in vivo. The molecular sequelae of isothiocyanate treatment in multiple myeloma cells were evaluated by multiplex analyses using bead arrays and western blotting.
  
  
  RESULTS
  We observed that sulforaphane and phenylethyl isothiocyanate have activity against myeloma cell lines and patients' myeloma cells both in vitro and in vivo using a myeloma xenograft mouse model. Isothiocyanates induced apoptotic death of myeloma cells; depletion of mitochondrial membrane potential; cleavage of PARP and caspases-3 and -9; as well as down-regulation of anti-apoptotic proteins including Mcl-1, X-IAP, c-IAP and survivin. Isothiocyanates induced G(2)/M cell cycle arrest accompanied by mitotic phosphorylation of histone H3. Multiplex analysis of phosphorylation of diverse components of signaling cascades revealed changes in MAPK activation; increased phosphorylation of c-jun and HSP27; as well as changes in the phosphorylation of Akt, and GSK3α/β and p53. Isothiocyanates suppressed proliferation of myeloma cells alone and when co-cultured with HS-5 stromal cells. Sulforaphane and phenylethyl isothiocyanate enhanced the in vitro anti-myeloma activity of several conventional and novel therapies used in multiple myeloma.
  
  
  CONCLUSIONS
  Our study shows that isothiocyanates have potent anti-myeloma activities and may enhance the activity of other anti-multiple myeloma agents. These results indicate that isothiocyanates may have therapeutic potential in multiple myeloma and provide the preclinical framework for future clinical studies of isothiocyanates in multiple myeloma.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dept. of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston MA 02115, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: David
authors.initials: D
authors.lastname: Cervi
authors.forename: Melissa
authors.initials: M
authors.lastname: Ooi
authors.forename: Kihyun
authors.initials: K
authors.lastname: Kim
authors.forename: Sabikun
authors.initials: S
authors.lastname: Nahar
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: Dana
authors.initials: D
authors.lastname: Cholujova
authors.forename: Merav
authors.initials: M
authors.lastname: Leiba
authors.forename: John F
authors.initials: JF
authors.lastname: Daley
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.forename: Simona
authors.initials: S
authors.lastname: Blotta
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlak
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000187:drug effects; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; C058305:phenethyl isothiocyanate; C016766:sulforaphane