-
Stefanie Tauber,
Alexander Jais,
Markus Jeitler,
Sandra Haider,
Julia Husa,
Josefine Lindroos,
Martin Knöfler, Matthias Mayerhofer,
Hubert Pehamberger,
Oswald Wagner,
Martin Bilban
-
Stefanie Tauber,
Alexander Jais,
Markus Jeitler,
Sandra Haider,
Julia Husa,
Josefine Lindroos,
Martin Knöfler, Matthias Mayerhofer,
Hubert Pehamberger,
Oswald Wagner,
Martin Bilban
-
Stefanie Tauber,
Alexander Jais,
Markus Jeitler,
Sandra Haider,
Julia Husa,
Josefine Lindroos,
Martin Knöfler, Matthias Mayerhofer,
Hubert Pehamberger,
Oswald Wagner,
Martin Bilban
-
Stefanie Tauber,
Alexander Jais,
Markus Jeitler,
Sandra Haider,
Julia Husa,
Josefine Lindroos,
Martin Knöfler, Matthias Mayerhofer,
Hubert Pehamberger,
Oswald Wagner,
Martin Bilban
-
Sabine Cerny-Reiterer,
Viviane Ghanim,
Gregor Hoermann,
Karl J Aichberger,
Harald Herrmann,
Leonhard Muellauer,
Andreas Repa,
Christian Sillaber,
Andrew F Walls, Matthias Mayerhofer,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
Neoplasia (New York, N.Y.) 07/2012; 14(7):572-84. · 5.48 Impact Factor
-
Peter Valent,
Gerald J Gleich,
Andreas Reiter,
Florence Roufosse,
Peter F Weller,
Andrzej Hellmann,
Georgia Metzgeroth,
Kristin M Leiferman,
Michel Arock,
Karl Sotlar,
Joseph H Butterfield,
Sabine Cerny-Reiterer, Matthias Mayerhofer,
Peter Vandenberghe,
Torsten Haferlach,
Bruce S Bochner,
Jason Gotlib,
Hans-Peter Horny,
Hans-Uwe Simon,
Amy D Klion
[show abstract]
[hide abstract]
ABSTRACT: Eosinophils and their products play an essential role in the pathogenesis of various reactive and neoplastic disorders. Depending on the underlying disease, molecular defect and involved cytokines, hypereosinophilia may develop and may lead to organ damage. In other patients, persistent eosinophilia is accompanied by typical clinical findings, but the causative role and impact of eosinophilia remain uncertain. For patients with eosinophil-mediated organ pathology, early therapeutic intervention with agents reducing eosinophil counts can be effective in limiting or preventing irreversible organ damage. Therefore, it is important to approach eosinophil disorders and related syndromes early by using established criteria, to perform all appropriate staging investigations, and to search for molecular targets of therapy. In this article, we review current concepts in the pathogenesis and evolution of eosinophilia and eosinophil-related organ damage in neoplastic and non-neoplastic conditions. In addition, we discuss classifications of eosinophil disorders and related syndromes as well as diagnostic algorithms and standard treatment for various eosinophil-related disorders.
Expert Review of Hematology 04/2012; 5(2):157-76. · 1.16 Impact Factor
-
Katharina Blatt,
Harald Herrmann,
Irina Mirkina,
Emir Hadzijusufovic,
Barbara Peter,
Sabine Strommer,
Gregor Hoermann, Matthias Mayerhofer,
Konrad Hoetzenecker,
Walter Klepetko,
Viviane Ghanim,
Katharina Marth,
Thorsten Füreder,
Volker Wacheck,
Rudolf Valenta,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring (3)H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC(50) values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1(nu) mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC(50) 0.5-1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.
PLoS ONE 01/2012; 7(1):e29925. · 4.09 Impact Factor
-
Gregor Hoermann,
Sabine Cerny-Reiterer,
Harald Herrmann,
Katharina Blatt,
Martin Bilban,
Heinz Gisslinger,
Bettina Gisslinger,
Leonhard Müllauer,
Robert Kralovics,
Christine Mannhalter,
Peter Valent, Matthias Mayerhofer
[show abstract]
[hide abstract]
ABSTRACT: The JAK2 mutation V617F is detectable in a majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Enforced expression of JAK2 V617F in mice induces myeloproliferation and bone marrow (BM) fibrosis, suggesting a causal role for the JAK2 mutant in the pathogenesis of MPNs. However, little is known about mechanisms and effector molecules contributing to JAK2 V617F-induced myeloproliferation and fibrosis. We show that JAK2 V617F promotes expression of oncostatin M (OSM) in neoplastic myeloid cells. Correspondingly, OSM mRNA levels were increased in the BM of patients with MPNs (median 287% of ABL, range 22-1450%) compared to control patients (median 59% of ABL, range 12-264%; P < 0.0001). OSM secreted by JAK2 V617F+ cells stimulated growth of fibroblasts and microvascular endothelial cells and induced the production of angiogenic and profibrogenic cytokines (HGF, VEGF, and SDF-1) in BM fibroblasts. All effects of MPN cell-derived OSM were blocked by a neutralizing anti-OSM antibody, whereas the production of OSM in MPN cells was suppressed by a pharmacologic JAK2 inhibitor or RNAi-mediated knockdown of JAK2. In summary, JAK2 V617F-mediated up-regulation of OSM may contribute to fibrosis, neoangiogenesis, and the cytokine storm observed in MPNs, suggesting that OSM might serve as a novel therapeutic target molecule in these neoplasms.
The FASEB Journal 11/2011; 26(2):894-906. · 5.71 Impact Factor
-
H Herrmann,
M Kneidinger,
S Cerny-Reiterer,
T Rülicke,
M Willmann,
K V Gleixner,
K Blatt,
G Hörmann,
B Peter,
P Samorapoompichit,
W Pickl,
G Y Bharate, M Mayerhofer,
W R Sperr,
H Maeda,
P Valent
[show abstract]
[hide abstract]
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.
Current cancer drug targets 10/2011; 12(1):51-63. · 5.13 Impact Factor
-
Karoline V Gleixner, Matthias Mayerhofer,
Sabine Cerny-Reiterer,
Gregor Hörmann,
Uwe Rix,
Keiryn L Bennett,
Emir Hadzijusufovic,
Renata A Meyer,
Winfried F Pickl,
Jason Gotlib,
Hans-Peter Horny,
Andreas Reiter,
Gerlinde Mitterbauer-Hohendanner,
Giulio Superti-Furga,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life expectancy. In both instances, neoplastic mast cells (MCs) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MCs in advanced SM and in the MC leukemia cell line HMC-1. Lyn and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MCs and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with 2 targeted drugs, dasatinib which blocks KIT, Lyn, and Btk activation in MCs, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT-independent signaling via Lyn/Btk contributes to growth of neoplastic MCs in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signaling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions.
Blood 06/2011; 118(7):1885-98. · 9.90 Impact Factor
-
Gregor Hoermann,
Sabine Cerny-Reiterer,
Andrea Perné,
Miriam Klauser,
Konrad Hoetzenecker,
Katharina Klein,
Leonhard Müllauer,
Marion Gröger,
Sebastian M B Nijman,
Walter Klepetko,
Peter Valent, Matthias Mayerhofer
[show abstract]
[hide abstract]
ABSTRACT: Systemic mastocytosis is a neoplastic disease of mast cells harboring the activating KIT mutation D816V. In most patients, mast cell infiltration in the bone marrow is accompanied by marked microenvironment alterations, including increased angiogenesis, osteosclerosis, and sometimes fibrosis. Little is known about the mast cell-derived molecules contributing to these bone marrow alterations. We show here that neoplastic mast cells in patients with systemic mastocytosis express oncostatin M (OSM), a profibrogenic and angiogenic modulator. To study the regulation of OSM expression, KIT D816V was inducibly expressed in Ba/F3 cells and was found to up-regulate OSM mRNA and protein levels, suggesting that OSM is a KIT D816V-dependent mediator. Correspondingly, KIT D816V(+) HMC-1.2 cells expressed significantly higher amounts of OSM than the KIT D816V(-) HMC-1.1 subclone. RNA interference-induced knockdown of STAT5, a key transcription factor in KIT D816V(+) mast cells, inhibited OSM expression in HMC-1 cells, whereas a constitutively activated STAT5 mutant induced OSM expression. Finally, OSM secreted from KIT D816V(+) mast cells stimulated growth of endothelial cells, fibroblasts, and osteoblasts, suggesting that mast cell-derived OSM may serve as a key modulator of the marrow microenvironment and thus contribute to the pathology of systemic mastocytosis.
American Journal Of Pathology 03/2011; 178(5):2344-56. · 4.89 Impact Factor
-
Wolfgang Warsch,
Karoline Kollmann,
Eva Eckelhart,
Sabine Fajmann,
Sabine Cerny-Reiterer,
Andrea Hölbl,
Karoline V Gleixner,
Michael Dworzak, Matthias Mayerhofer,
Gregor Hoermann,
Harald Herrmann,
Christian Sillaber,
Gerda Egger,
Peter Valent,
Richard Moriggl,
Veronika Sexl
[show abstract]
[hide abstract]
ABSTRACT: In BCR-ABL1(+) leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1(+) cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-β, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph(+) chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1(+) leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1(+) leukemia.
Blood 01/2011; 117(12):3409-20. · 9.90 Impact Factor
-
Karoline V Gleixner,
Veronika Ferenc,
Barbara Peter,
Alexander Gruze,
Renata A Meyer,
Emir Hadzijusufovic,
Sabine Cerny-Reiterer, Matthias Mayerhofer,
Winfried F Pickl,
Christian Sillaber,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: In most patients with chronic myeloid leukemia (CML), the disease can be kept under control using the BCR/ABL kinase inhibitor imatinib. Nevertheless, resistance or intolerance to imatinib and other BCR/ABL inhibitors may occur during therapy. Therefore, CML research is focusing on novel targets and targeted drugs. Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays an essential role in mitosis. In this study, we examined the expression of Plk1 in CML cells and its potential role as a therapeutic target. Plk1 was found to be expressed in phosphorylated form in the CML cell line K562 as well as in primary CML cells in all patients tested. Inhibition of BCR/ABL by imatinib or nilotinib (AMN107) led to decreased expression of the Plk1 protein in CML cells, suggesting that BCR/ABL promotes Plk1 generation. Silencing of Plk1 in CML cells by a small interfering RNA approach was followed by cell cycle arrest and apoptosis. Furthermore, the Plk1-targeting drug BI 2536 was found to inhibit proliferation of imatinib-sensitive and imatinib-resistant CML cells, including leukemic cells, carrying the T315 mutation of BCR/ABL with reasonable IC(50) values (1-50 nmol/L). The growth-inhibitory effects of BI 2536 on CML cells were found to be associated with cell cycle arrest and apoptosis. Moreover, BI 2536 was found to synergize with imatinib and nilotinib in producing growth inhibition in CML cells. In conclusion, Plk1 is expressed in CML cells and may represent a novel, interesting target in imatinib-sensitive and imatinib-resistant CML.
Cancer Research 02/2010; 70(4):1513-23. · 7.86 Impact Factor
-
Stefanie Tauber,
Alexander Jais,
Markus Jeitler,
Sandra Haider,
Julia Husa,
Josefine Lindroos,
Martin Knöfler, Matthias Mayerhofer,
Hubert Pehamberger,
Oswald Wagner,
Martin Bilban
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
Heme Oxygenase-1 (HO-1) is expressed in many cancers and promotes growth and survival of neoplastic cells. Recently, HO-1 has been implicated in tumor cell invasion and metastasis. However, the molecular mechanisms underlying these biologic effects of HO-1 remain largely unknown. To identify a common mechanism of action of HO-1 in cancer, we determined the global effect of HO-1 on the transcriptome of multiple tumor entities and identified a universal HO-1-associated gene expression signature.
Results
Genome-wide expression profiling of Heme Oxygenase-1 expressing versus HO-1 silenced BeWo choriocarcinoma cells as well as a comparative meta-profiling of the preexisting expression database of 190 human tumors of 14 independent cancer types led to the identification of 14 genes, the expression of which correlated strongly and universally with that of HO-1 (P = 0.00002). These genes included regulators of cell plasticity and extracellular matrix (ECM) remodeling (MMP2, ADAM8, TGFB1, BGN, COL21A1, PXDN), signaling (CRIP2, MICB), amino acid transport and glycosylation (SLC7A1 and ST3GAL2), estrogen and phospholipid biosynthesis (AGPAT2 and HSD17B1), protein stabilization (IFI30), and phosphorylation (ALPPL2). We selected PXDN, an adhesion molecule involved in ECM formation, for further analysis and functional characterization. Immunofluorescence and Western blotting confirmed the positive correlation of expression of PXDN and HO-1 in BeWo cancer cells as well as co-localization of these two proteins in invasive extravillous trophoblast cells. Modulation of HO-1 expression in both loss-of and gain-of function cell models (BeWo and 607B melanoma cells, respectively) demonstrated a direct relationship of HO-1 expression with cell adhesion to Fibronectin and Laminin coated wells. The adhesion-promoting effects of HO-1 were dependent on PXDN expression, as loss of PXDN in HO-1 expressing BeWo and 607B cells led to reduced cell attachment to Laminin and Fibronectin coated wells.
Conclusions
Collectively, our results show that HO-1 expression determines a distinct 'molecular signature' in cancer cells, which is enriched in genes associated with tumorigenesis. The protein network downstream of HO-1 modulates adhesion, signaling, transport, and other critical cellular functions of neoplastic cells and thus promotes tumor cell growth and dissemination.
Molecular Cancer 01/2010; · 3.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mammalian target of rapamycin (mTOR) has recently been identified as a potential target in acute myeloid leukemia (AML).
We treated 5 patients with chemotherapy-refractory AML with the mTOR-inhibitor rapamycin at 2mg per os daily for 14 days, with dose adjustment allowed to reach a target serum rapamycin concentration of 10-20 ng/mL. Four of five patients received additional hydroxyurea at constant dose during treatment with rapamycin.
Two patients achieved a leukocyte response, in one of them, a prolonged response was seen. In the other patients, blast counts remained stable or increased during rapamycin therapy. We did not observe severe hematologic or non-hematologic side effects of rapamycin.
Rapamycin at 2mg per day acts mildly cytoreductive in a subgroup of patients with refractory AML. Higher doses and drug combinations may be required to obtain long lasting anti-leukemic effects in these patients.
European Journal of Internal Medicine 12/2009; 20(8):775-8. · 2.00 Impact Factor
-
Christian Baumgartner,
Sabine Cerny-Reiterer,
Karoline Sonneck, Matthias Mayerhofer,
Karoline V Gleixner,
Richard Fritz,
Marc Kerenyi,
Cedric Boudot,
Fabrice Gouilleux,
Jan-Wilhelm Kornfeld,
Christian Sillaber,
Richard Moriggl,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: Recent data suggest that the signal transducer and activator of transcription (STAT)5 contributes to differentiation and growth of mast cells. It has also been described that constitutively phosphorylated STAT5 (pSTAT5) plays a pro-oncogenic role in various myeloid neoplasms. We examined the expression of pSTAT5 in neoplastic mast cells in systemic mastocytosis and asked whether the disease-related oncoprotein KIT D816V is involved in STAT5 activation. As assessed by immunohistochemistry using the anti-pSTAT5 antibody AX1, neoplastic mast cells were found to display pSTAT5 in all SM patients examined (n = 40). Expression of pSTAT5 was also demonstrable in the KIT D816V-positive mast cell leukemia cell line HMC-1. Using various staining-protocols, pSTAT5 was found to be located in both the cytoplasmic and nuclear compartment of mast cells. To define the functional role of KIT D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of KIT D816V were used. In these cells, induction of KIT D816V resulted in an increased expression of pSTAT5 without substantial increase in total STAT5. Moreover, the KIT D816V-targeting kinase-inhibitor PKC412 was found to counteract expression of pSTAT5 in HMC-1 cells as well as doxycycline-induced expression of pSTAT5 in Ba/F3 cells. Finally, a dominant negative STAT5-construct was found to inhibit growth of HMC-1 cells. Together, our data show that neoplastic mast cells express cytoplasmic and nuclear pSTAT5, that KIT D816V promotes STAT5-activation, and that STAT5-activation contributes to growth of neoplastic mast cells.
American Journal Of Pathology 11/2009; 175(6):2416-29. · 4.89 Impact Factor
-
Karl J Aichberger,
Karoline V Gleixner,
Irina Mirkina,
Sabine Cerny-Reiterer,
Barbara Peter,
Veronika Ferenc,
Michael Kneidinger,
Christian Baumgartner, Matthias Mayerhofer,
Alexander Gruze,
Winfried F Pickl,
Christian Sillaber,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MCs. Recent data suggest that the proapoptotic BH3-only death regulator Bim plays a role as a tumor suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816-induced down-regulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and promote expression of Bim in MC leukemia cell lines HMC-1.1 (D816V negative) and HMC-1.2 (D816V positive). Both drugs were also found to counteract growth of primary neoplastic MCs. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Our data show that KIT D816V suppresses expression of proapoptotic Bim in neoplastic MCs. Targeting of Bcl-2 family members by drugs promoting Bim (re)-expression, or by BH3-mimetics such as obatoclax, may be an attractive therapy concept in SM.
Blood 10/2009; 114(26):5342-51. · 9.90 Impact Factor
-
K V Gleixner, M Mayerhofer,
A Vales,
A Gruze,
G Hörmann,
S Cerny-Reiterer,
E Lackner,
E Hadzijusufovic,
H Herrmann,
A K Iyer,
M-T Krauth,
W F Pickl,
B Marian,
R Panzer-Grümayer,
C Sillaber,
H Maeda,
C Zielinski,
P Valent
[show abstract]
[hide abstract]
ABSTRACT: Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.
Current cancer drug targets 09/2009; 9(5):675-89. · 5.13 Impact Factor
-
Andrea Perne,
Markus K Muellner,
Magdalena Steinrueck,
Nils Craig-Mueller,
Julia Mayerhofer,
Ilse Schwarzinger,
Mathew Sloane,
Iris Z Uras,
Gregor Hoermann,
Sebastian M B Nijman, Matthias Mayerhofer
[show abstract]
[hide abstract]
ABSTRACT: Cardiac glycosides are Na(+)/K(+)-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive.
Using an unbiased transcriptomics approach, we found that cardiac glycosides inhibit general protein synthesis. Protein synthesis inhibition and cytotoxicity were not specific for cancer cells as they were observed in both primary and cancer cell lines. These effects were dependent on the Na(+)/K(+)-pump as they were rescued by expression of a cardiac glycoside-resistant Na(+)/K(+)-pump. Unlike human cells, rodent cells are largely resistant to cardiac glycosides in vitro and mice were found to tolerate extremely high levels.
The physiological difference between human and mouse explains the previously observed sensitivity of human cancer cells in mouse xenograft experiments. Thus, published mouse xenograft models used to support anti-tumor activity for these drugs require reevaluation. Our finding that cardiac glycosides inhibit protein synthesis provides a mechanism for the cytotoxicity of CGs and raises concerns about ongoing clinical trials to test CGs as anti-cancer agents in humans.
PLoS ONE 01/2009; 4(12):e8292. · 4.09 Impact Factor
-
Emir Hadzijusufovic,
Laura Rebuzzi,
Karoline V Gleixner,
Veronika Ferenc,
Barbara Peter,
Rudin Kondo,
Alexander Gruze,
Michael Kneidinger,
Maria-Theresa Krauth, Matthias Mayerhofer,
Puchit Samorapoompichit,
Khaled Greish,
Arun K Iyer,
Winfried F Pickl,
Hiroshi Maeda,
Michael Willmann,
Peter Valent
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
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.
Experimental Hematology 09/2008; 36(11):1461-70. · 2.90 Impact Factor
