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.
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.
Baumann
Philipp
P
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Germany. Philipp.Baumann@med.uni-muenchen.de
Hagemeier
Hilke
H
Mandl-Weber
Sonja
S
Franke
Daniel
D
Schmidmaier
Ralf
R
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus