title: The Hsp32 inhibitors SMA-ZnPP and PEG-ZnPP exert major growth-inhibitory effects on D34+/CD38+ and CD34+/CD38- AML progenitor cells.
abstract: Heat shock protein 32 (Hsp32), also known as heme oxygenase 1 (HO-1), has recently been identified as a potential target in various hematologic malignancies. We provide evidence that Hsp32 is constitutively expressed in primary leukemic cells in patients with acute myeloid leukemia (AML) and in various AML cell lines (HL60, U937, KG1). Expression of Hsp32 mRNA was demonstrable by qPCR, and expression of the Hsp32 protein by immunocytochemistry and Western blotting. The stem cell-enriched CD34+/CD38+ and CD34+/CD38- fractions of AML cells were found to express Hsp32 mRNA in excess over normal CD34+ progenitor cells. Two Hsp32-targeting drugs, pegylated zinc-protoporphyrin (PEG-ZnPP) and styrene-maleic-acid-copolymer-micelle-encapsulated ZnPP (SMAZnPP), were found to inhibit cytokine-dependent and spontaneous proliferation in all 3 AML cell lines as well as in primary AML cells. Growth inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-dependent with IC50 values ranging between 1 and 20 μM, and were accompanied by apoptosis as evidenced by light- and electron microscopy, Tunel assay, and caspase-3 activation. Finally, we were able to demonstrate that SMA-ZnPP inhibits cytokine-dependent proliferation of CD34+/CD38+ and CD34+/CD38- AML progenitor cells in vitro in all patients as well as leukemiainitiation of AML stem cells in NOD-SCID IL-2Rγ(-/-) (NSG) mice in vivo. Together, our data suggest that Hsp32 plays an important role as a survival factor in leukemic stem cells and as a potential new target in AML.
authors.affiliation: Ludwig-Boltzmann Cluster Oncology, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Herrmann
authors.forename: M
authors.initials: M
authors.lastname: Kneidinger
authors.forename: S
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: T
authors.initials: T
authors.lastname: Rülicke
authors.forename: M
authors.initials: M
authors.lastname: Willmann
authors.forename: K V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: K
authors.initials: K
authors.lastname: Blatt
authors.forename: G
authors.initials: G
authors.lastname: Hörmann
authors.forename: B
authors.initials: B
authors.lastname: Peter
authors.forename: P
authors.initials: P
authors.lastname: Samorapoompichit
authors.forename: W
authors.initials: W
authors.lastname: Pickl
authors.forename: G Y
authors.initials: GY
authors.lastname: Bharate
authors.forename: M
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: W R
authors.initials: WR
authors.lastname: Sperr
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: P
authors.initials: P
authors.lastname: Valent
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018922:HL-60 Cells; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology* / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D011137:Polystyrenes / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D018952:Antigens, CD34; D006131:Growth Inhibitors; D008298:Maleates; D008562:Membrane Glycoproteins; D008665:Metalloporphyrins; D011137:Polystyrenes; C518727:copoly(styrene-maleic acid)-zinc protoporphyrin; C476103:pegylated zinc protoporphyrin; D011092:Polyethylene Glycols; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1