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ABSTRACT: Heat shock protein 90 (HSP90) binds and stabilizes numerous proteins and kinases essential for myeloma cell survival and proliferation. We and others have recently demonstrated that inhibition of HSP90 by small molecular mass inhibitors induces cell death in multiple myeloma (MM). However, some of the HSP90 inhibitors involved in early clinical trials have shown limited antitumor activity and unfavorable toxicity profiles. Here, we analyzed the effects of the novel, orally bioavailable HSP90 inhibitor NVP-HSP990 on MM cell proliferation and survival. The inhibitor led to a significant reduction in myeloma cell viability and induced G2 cell cycle arrest, degradation of caspases-8 and -3 and induction of apoptosis. Inhibition of the HSP90 ATPase activity was accompanied by degradation of MM phospho-Akt and phospho-ERK1/2 and upregulation of Hsp70. Exposure of MM cells to a combination of NVP-HSP990 and either melphalan or histone deacetylase (HDAC) inhibitors caused synergistic inhibition of viability, increased induction of apoptosis and was able to overcome the primary resistance of the cell line RPMI-8226 to HSP90 inhibition. Combined incubation with melphalan and NVP-HSP990 led to synergistically increased cleavage of caspases-2, -9 and -3. These data demonstrate promising activity for NVP-HSP990 as single agent or combination treatment in MM and provide a rationale for clinical trials. (c) 2012 John Wiley & Sons A/S.
European Journal Of Haematology 02/2012; · 2.61 Impact Factor
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ABSTRACT: Breath gas analysis offers fascinating new opportunities as it is completely noninvasive and provides a unique window to various biochemical processes in the organism. Requirements for clinical application of this innovative technique include on site and point of care applicability. As most analytical methods like sensors are often not fast enough to realize breath-to-breath sampling additional effort is necessary to provide breath samples of well defined and reproducible composition. For that purpose, we built an automatic CO<sub>2</sub> controlled device from standard industrial components that enables adjustable breath sampling in any phase of expiration. Control of sampling was realized by fast responding infrared CO<sub>2</sub> sensors. The electrical signal of these sensors was used to trigger a micro pump and a valve. In order to render the device as versatile as possible direct coupling with sensors as well as continuous or discrete sampling via a sample loop or traps was possible. CO<sub>2</sub> concentrations, gas flow, and sample volumes were continuously recorded. Reliability and reproducibility of the device were evaluated and compared with an already established and validated manual sampling method. Alveolar concentrations of selected volatile organic compounds (VOCs) were determined in the corresponding samples taken in rest and during treadmill exercise. Substance concentrations of breath biomarkers in the automatically and manually collected alveolar samples were identical. Reliable sampling was possible with the automatic device up to respiratory rates of 40/min. Controlled and versatile alveolar sampling represents an indispensable requirement of application of most analytical methods and sensor technology in breath analysis.
IEEE Sensors Journal 02/2010; · 1.52 Impact Factor
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C Jakob,
J Sterz,
P Liebisch, M Mieth,
J Rademacher,
A Goerke,
U Heider,
C Fleissner,
M Kaiser,
I von Metzler,
C Müller,
O Sezer
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 22(9):1812. · 8.30 Impact Factor
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I von Metzler,
H Krebbel,
M Hecht,
R A Manz,
C Fleissner, M Mieth,
M Kaiser,
C Jakob,
J Sterz,
L Kleeberg,
U Heider,
O Sezer
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ABSTRACT: In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
Leukemia 10/2007; 21(9):2025-34. · 9.56 Impact Factor
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ABSTRACT: Undercutting of polysilicon overetched in fluorine‐based plasmas has been limited to 0.1 μ per edge by adding small amounts of CFCl 3 to SF 6 . This 0.1 μ undercut occurs during the initial etching stage and does not increase with overetch. To test possible mechanisms, these experiments were repeated with CHF 3 and Cl 2 used in place of CFCl 3 . It was found that Cl and photoresist are responsible for passivating the sidewalls of the polysilcon lines. This passivation is relatively insensitive to exact amount of CFCl 3 added. Etch rate measurements were made for polysilicon, SiO 2 , and AZ 1470 photoresist and found to be essentially indistinguishable from those obtained in pure SF 6 etching, thus the fast polysilicon etch rate and good selectivity characteristics of SF 6 etching are preserved. The ability to etch polysilicon without sacrificing linewidth, selectivity, or etch rate makes CFCl 3 /SF 6 plasma etching very useful for VLSI processing.
Journal of Vacuum Science & Technology A Vacuum Surfaces and Films 05/1983; · 1.25 Impact Factor
