title: Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors.
abstract: BACKGROUND
  Heat shock proteins (HSPs) are molecular chaperones that assist proteins in their folding to native structures. HSP90, and more recently HSP70, have emerged as possible therapeutic targets in human malignancies, including acute myeloid leukemia (AML).
  
  
  METHODS
  The authors investigated the effects of the HSP70 inhibitor VER-155008 tested alone or in combination with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) on proliferation, viability, constitutive cytokine release and intracellular HSP levels of primary human AML cells.
  
  
  RESULTS
  VER-155008 caused a dose-dependent inhibition of cytokine-dependent AML cell proliferation both in suspension cultures and in a colony formation assay, and the drug also had a proapoptotic effect. HSP70 and HSP90 inhibition had additive antiproliferative and proapoptotic effects. VER-155008 caused a strong inhibition of the constitutive AML cell release of several growth factors/regulators of hematopoiesis (i.e., TNF-α, VEGF, IL-3, IL-1β, IL-1 receptor antagonist), but had relatively weak effects on the constitutive chemokine release. HSP70 inhibition did not induce any compensatory increase of other HSPs.
  
  
  CONCLUSIONS
  HSP70 inhibition has antileukemic effects when tested alone, and the combination of HSP70 and HSP90 inhibition seems to have additive antileukemic effects for primary human AML cells in vitro.
authors.affiliation: University of Bergen, Department of Clinical Science, Division for Hematology, Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.forename: Ina
authors.initials: I
authors.lastname: Nepstad
authors.forename: André
authors.initials: A
authors.lastname: Sulen
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Kimberley Joanne
authors.initials: KJ
authors.lastname: Hatfield
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011684:Purine Nucleosides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011684:Purine Nucleosides; C550733:VER 155008; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin