title: Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment.
abstract: OBJECTIVE
  We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells.
  
  
  METHODS
  MM cell lines were incubated with perifosine (5 and 10 micromol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination.
  
  
  RESULTS
  The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin.
  
  
  CONCLUSIONS
  This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester, Rochester, New York, USA.
authors.forename: Alissa
authors.initials: A
authors.lastname: Huston
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jia
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Moreau
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Judith
authors.initials: J
authors.lastname: Runnels
authors.forename: Judy
authors.initials: J
authors.lastname: Anderson
authors.forename: Yazan
authors.initials: Y
authors.lastname: Alsayed
authors.forename: Aldo
authors.initials: A
authors.lastname: Roccaro
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Hatjiharissi
authors.forename: Yu-Tsu
authors.initials: YT
authors.lastname: Tai
authors.forename: Peter
authors.initials: P
authors.lastname: Sportelli
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: David G
authors.initials: DG
authors.lastname: Roodman
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004261:DNA Replication / Q000187:drug effects; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009101:Multiple Myeloma / Q000473:pathology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt