PMID- 19071109
OWN - NLM
STAT- MEDLINE
DCOM- 20090227
LR  - 20211203
IS  - 1090-2422 (Electronic)
IS  - 0014-4827 (Linking)
VI  - 315
IP  - 3
DP  - 2009 Feb 1
TI  - The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian 
      target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple 
      myeloma.
PG  - 485-97
LID - 10.1016/j.yexcr.2008.11.007 [doi]
AB  - NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and 
      mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is 
      currently being evaluated in a phase I/II clinical trial. Here we show that 
      NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary 
      myeloma cells at nanomolar concentrations in a time and dose dependent fashion. 
      Further experiments revealed induction of apoptosis in three of four cell lines. 
      Inhibition of cell growth was mainly due to inhibition of myeloma cell 
      proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction 
      of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin 
      D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B 
      (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of 
      CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) 
      and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely 
      abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and 
      additive activity of NVP-BEZ235 together with melphalan, doxorubicin and 
      bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly 
      effective and NVP-BEZ235 represents a potential new candidate for targeted 
      therapy in multiple myeloma.
FAU - Baumann, Philipp
AU  - Baumann P
AD  - Department of Hematology and Oncology Medizinische Klinik Innenstadt, Klinikum 
      der Universitat Munchen, Germany. Philipp.Baumann@med.uni-muenchen.de
FAU - Mandl-Weber, Sonja
AU  - Mandl-Weber S
FAU - Oduncu, Fuat
AU  - Oduncu F
FAU - Schmidmaier, Ralf
AU  - Schmidmaier R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081127
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pyrazines)
RN  - 0 (Quinolines)
RN  - 0 (Recombinant Proteins)
RN  - 69G8BD63PP (Bortezomib)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - Q41OR9510P (Melphalan)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Doxorubicin/pharmacology
MH  - Drug Synergism
MH  - G1 Phase/drug effects
MH  - Humans
MH  - Imidazoles/administration & dosage/*pharmacology
MH  - Melphalan/pharmacology
MH  - Multiple Myeloma
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrazines/pharmacology
MH  - Quinolines/administration & dosage/*pharmacology
MH  - Recombinant Proteins/pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - TOR Serine-Threonine Kinases
EDAT- 2008/12/17 09:00
MHDA- 2009/02/28 09:00
CRDT- 2008/12/17 09:00
PHST- 2008/07/10 00:00 [received]
PHST- 2008/11/12 00:00 [revised]
PHST- 2008/11/17 00:00 [accepted]
PHST- 2008/12/17 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/02/28 09:00 [medline]
AID - S0014-4827(08)00498-9 [pii]
AID - 10.1016/j.yexcr.2008.11.007 [doi]
PST - ppublish
SO  - Exp Cell Res. 2009 Feb 1;315(3):485-97. doi: 10.1016/j.yexcr.2008.11.007. Epub 
      2008 Nov 27.