PMID- 22299028
OWN - NLM
STAT- MEDLINE
DCOM- 20120705
LR  - 20220129
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 1
DP  - 2012
TI  - The PI3-kinase/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent 
      activation of human mast cells and basophils.
PG  - e29925
LID - 10.1371/journal.pone.0029925 [doi]
LID - e29925
AB  - 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 microM) and 
      the HMC-1.2 subclone expressing KIT D816V (0.005 microM). 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 microM) 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.
FAU - Blatt, Katharina
AU  - Blatt K
AD  - Division of Hematology and Hemostaseology, Department of Internal Medicine I, 
      Medical University of Vienna, Vienna, Austria.
FAU - Herrmann, Harald
AU  - Herrmann H
FAU - Mirkina, Irina
AU  - Mirkina I
FAU - Hadzijusufovic, Emir
AU  - Hadzijusufovic E
FAU - Peter, Barbara
AU  - Peter B
FAU - Strommer, Sabine
AU  - Strommer S
FAU - Hoermann, Gregor
AU  - Hoermann G
FAU - Mayerhofer, Matthias
AU  - Mayerhofer M
FAU - Hoetzenecker, Konrad
AU  - Hoetzenecker K
FAU - Klepetko, Walter
AU  - Klepetko W
FAU - Ghanim, Viviane
AU  - Ghanim V
FAU - Marth, Katharina
AU  - Marth K
FAU - Fureder, Thorsten
AU  - Fureder T
FAU - Wacheck, Volker
AU  - Wacheck V
FAU - Valenta, Rudolf
AU  - Valenta R
FAU - Valent, Peter
AU  - Valent P
LA  - eng
GR  - F 4605/FWF_/Austrian Science Fund FWF/Austria
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120127
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Antibody-Dependent Cell Cytotoxicity/*drug effects
MH  - Basophils/*drug effects/immunology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Down-Regulation/drug effects
MH  - Female
MH  - Humans
MH  - Imidazoles/adverse effects/*pharmacology
MH  - Immunoglobulin E/immunology/metabolism/pharmacology/*physiology
MH  - Male
MH  - Mast Cells/*drug effects/immunology
MH  - Mice
MH  - Mice, Nude
MH  - Middle Aged
MH  - Molecular Targeted Therapy/adverse effects
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Quinolines/adverse effects/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC3267720
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts: Dr. Valent received a research grant from Novartis. The 
      authors declare no other conflict of interest. This does not alter the authors' 
      adherence to all the PLoS ONE policies on sharing data and materials.
EDAT- 2012/02/03 06:00
MHDA- 2012/07/06 06:00
PMCR- 2012/01/27
CRDT- 2012/02/03 06:00
PHST- 2011/07/08 00:00 [received]
PHST- 2011/12/07 00:00 [accepted]
PHST- 2012/02/03 06:00 [entrez]
PHST- 2012/02/03 06:00 [pubmed]
PHST- 2012/07/06 06:00 [medline]
PHST- 2012/01/27 00:00 [pmc-release]
AID - PONE-D-11-12882 [pii]
AID - 10.1371/journal.pone.0029925 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(1):e29925. doi: 10.1371/journal.pone.0029925. Epub 2012 Jan 27.