PMID- 19240643
OWN - NLM
STAT- MEDLINE
DCOM- 20090515
LR  - 20211203
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 20
IP  - 4
DP  - 2009 Apr
TI  - Myeloma cell growth inhibition is augmented by synchronous inhibition of the 
      insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian 
      target of rapamycin by Rad001.
PG  - 259-66
LID - 10.1097/CAD.0b013e328328d18b [doi]
AB  - Multiple myeloma is still incurable. Myeloma cells become resistant to common 
      drugs and patients eventually die of tumour progression. Therefore, new targets 
      and drugs are needed immediately. NVP-AEW541 is a new, orally bioavailable small 
      molecule inhibitor of the insulin-like growth factor-1 receptor (IGF-1R). Here, 
      we show that NVP-AEW541 inhibits cell growth in myeloma cells at low 
      concentrations in a time-dependent and a dose-dependent manner. Further 
      experiments using the annexin-V-fluorescein isothiocyanate/propidium iodide assay 
      revealed induction of apoptosis in common myeloma cell lines, but not in 
      peripheral blood mononuclear cell from healthy donors. Stimulation of myeloma 
      cells with IGF-1 led to a vast increase of cell growth and this was blocked by 
      low doses of NVP-AEW541. Stimulation of myeloma cells with conditioned medium 
      obtained from a 48-h-old HS-5 stromal cell culture was only partly blocked by 
      NVP-AEW541. Western blotting experiments revealed that NVP-AEW541 decreased the 
      phosphorylation status of P70S6 kinase and 4E-BP-1 but not of mammalian target of 
      rapamycin (mTOR). Combined inhibition of IGF-1R and mTOR using the novel mTOR 
      inhibitor Rad001 led to additive/synergistic increase of cell growth inhibition 
      in multiple myeloma cells, which was accompanied by a stronger dephosphorylation 
      of P70S6 kinase and 4E-BP-1. Taken together, we show that the combined inhibition 
      of IGF-1R and mTOR by combining NVP-AEW541 and Rad001 is highly effective in 
      multiple myeloma and might represent a potential new treatment strategy.
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 - Hagemeier, Hilke
AU  - Hagemeier H
FAU - Mandl-Weber, Sonja
AU  - Mandl-Weber S
FAU - Franke, Daniel
AU  - Franke D
FAU - Schmidmaier, Ralf
AU  - Schmidmaier R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (NVP-AEW541)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & 
      dosage/*pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems
MH  - Drug Synergism
MH  - Everolimus
MH  - Humans
MH  - Multiple Myeloma/*drug therapy/pathology
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*drug effects/metabolism
MH  - Pyrimidines/administration & dosage
MH  - Pyrroles/administration & dosage
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
EDAT- 2009/02/26 09:00
MHDA- 2009/05/16 09:00
CRDT- 2009/02/26 09:00
PHST- 2009/02/26 09:00 [entrez]
PHST- 2009/02/26 09:00 [pubmed]
PHST- 2009/05/16 09:00 [medline]
AID - 10.1097/CAD.0b013e328328d18b [doi]
PST - ppublish
SO  - Anticancer Drugs. 2009 Apr;20(4):259-66. doi: 10.1097/CAD.0b013e328328d18b.