作者: Peter, Barbara ; Pickl, Winfried F. ; Jäger, Ulrich ; Gleixner, Karoline V. ; Cerny-Reiterer, Sabine ; Herrmann, Harald ; Sperr, Wolfgang R. ; Hadzijusufovic, Emir ; Meyer, Renata A. ; Melo, Junia V. ; Maeda, Hiroshi ; Stefanzl, Gabriele ; Valent, Peter

Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph+ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34+/CD38- ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1+ cell lines, in Ph- lymphoblastic cell lines and in primary Ph+ and Ph- ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph+ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph+ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.

2012-01-01·Current cancer drug targets4区 · 医学

The Hsp32 Inhibitors SMA-ZnPP and PEG-ZnPP Exert Major Growth-Inhibitory Effects on D34+/CD38+ and CD34+/CD38- AML Progenitor Cells

4区 · 医学

Article

作者: Sperr, W. R. ; Valent, P. ; Maeda, H. ; Herrmann, H. ; Blatt, K. ; Samorapoompichit, P. ; Gleixner, K. V. ; Mayerhofer, M. ; Willmann, M. ; Cerny-Reiterer, S. ; Hoermann, G. ; Peter, B. ; Kneidinger, M. ; Bharate, G. Y. ; Pickl, W. ; Ruelicke, T.

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.

2008-11-01·Experimental hematology4区 · 医学

Targeting of heat-shock protein 32/heme oxygenase-1 in canine mastocytoma cells is associated with reduced growth and induction of apoptosis

4区 · 医学

Article

作者: Laura Rebuzzi ; Alexander Gruze ; Matthias Mayerhofer ; Barbara Peter ; Michael Kneidinger ; Arun K. Iyer ; Peter Valent ; Michael Willmann ; Winfried F. Pickl ; Maria Theresa Krauth ; Hiroshi Maeda ; Emir Hadzijusufovic ; Rudin Kondo ; Puchit Samorapoompichit ; Veronika Ferenc ; Khaled Greish ; Karoline V. Gleixner

OBJECTIVE:

Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. Therefore, current research focuses on new targets in neoplastic MC and development of respective targeted drugs. Mastocytomas in dogs often behave as aggressive tumors. We report that heat-shock protein 32 (Hsp32), also known as heme oxygenase-1, is a survival-enhancing molecule and new target in canine mastocytoma cells.

MATERIALS AND METHODS:

As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, immunocytochemistry, and Western blotting, primary neoplastic dog MC, and the canine mastocytoma-derived cell line C2 expressed Hsp32 mRNA and the Hsp32 protein in a constitutive manner.

RESULTS:

The KIT-targeting drug midostaurin inhibited expression of Hsp32, as well as survival in C2 cells. Confirming the functional role of Hsp32, the inhibitory effect of midostaurin on C2 cells was markedly reduced by the Hsp32-inductor hemin. Two pharmacologic Hsp32-inhibitors, styrene maleic-acid micelle-encapsulated ZnPP (SMA-ZnPP) and pegylated zinc-protoporphyrin (PEG-ZnPP) were applied. Both drugs were found to inhibit proliferation of C2 cells as well as growth of primary neoplastic canine MC. The growth-inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose- and time-dependent (IC(50): 1-10 muM) and found to be associated with induction of apoptosis.

CONCLUSIONS:

Hsp32 is an important survival factor and interesting new target in neoplastic canine MC. Trials with Hsp32-targeted drugs are now warranted to define the clinical efficacy of these drugs.

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